Chroman derivatives having estrogen receptor degradation activity and uses thereof

ABSTRACT

The present disclosure relates to novel compounds, pharmaceutical compositions containing such compounds, and their use in prevention and treatment of cancer and related diseases and conditions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 16/846,492,filed Apr. 13, 2020, which claims priority to U.S. Provisional PatentApplication No. 62/947,213 filed on Dec. 12, 2019. The contents of thetwo applications are incorporated herein by reference.

FIELD OF THE DISCLOSURE

The present disclosure relates to novel compounds, pharmaceuticalcompositions containing such compounds, and their use in prevention andtreatment of diseases and conditions, e.g., cancer.

BACKGROUND OF THE DISCLOSURE

Estrogen, a female sex hormone, through binding to its cognate Estrogenreceptors, ERα and ERβ, governs a wide range of physiological processes,e.g., the development of the female reproductive system, the maintenanceof bone mass, and the protection of cardiovascular tissue and thecentral nervous system. Upon estrogen's binding to an estrogen receptor(“ER”), the receptor undergoes a conformational change resulting in itshomodimerization. The ER homodimer then binds to estrogen-responseelements (“EREs”) that are present in the promoters of a specific set oftarget genes and regulates their expression with the help oftranscriptional coregulators. Several thousand canonical ER target geneshave been identified, many of which regulate cell proliferation andsurvival.

Because ER signaling is implicated in many pathways, it is well knownthat deregulation of ER signaling, specifically through ERα, results inuncontrolled cellular proliferation which eventually results intocancer. ER+ breast cancer accounts for approximately 75% of all breastcancers diagnosed, as well as some ovarian and endometrial cancers. Theprevalence of ER+ cancer has led to decades of investigation anddevelopment of antiestrogens as therapeutic agents.

Antiestrogen (i.e., hormonal) therapy is the first choice for treatmentof most ER+ breast cancers. There are three major classes ofantiestrogen therapies, including aromatase inhibitors (e.g., letrozoleand anastrozole); selective estrogen modulators (e.g., tamoxifen,toremifene, and raloxifene); and selective estrogen receptor degraders(e.g., fulvestrant). These classes of antiestrogen therapy operate bydifferent mechanisms of action, such as inhibiting aromatase enzyme,competitively binding to ERα, and/or causing ERα degradation.

The aforementioned therapies may result in deleterious effects. Forexample, administration of aromatase inhibitors results in a decrease inbone mineral density, which can result in an increased risk offractures. Administration of selective estrogen modulators can result indevelopment of endometrial cancer and/or cardiovascular issues, e.g.,deep thrombosis and pulmonary embolism. Additionally, the aforementionedtherapies may suffer from insufficient clinical efficacy.

Accordingly, there exists a need to treat ER+ cancer without the harmfulside effects known for current therapies. One approach to achieve thisgoal would be to utilize the naturally occurring cellularubiquitin-mediated degradation. Without being bound to any theory, it isbelieved that ERα degradation may occur when both ERα and a ubiquitinligase are bound and brought into close proximity.

Cereblon (“CRBN”) E3 ubiquitin ligase is a ubiquitin ligase that CRBNforms an E3 ubiquitin ligase complex with damaged DNA binding protein 1and Cullin 4. It functions as a substrate receptor by bringing thesubstrates to close proximity for ubiquitination and subsequentdegradation by proteasomes. Recently, it has been discovered that smallmolecules drugs, e.g., thalidomide and its close analogs, lenalidomideand pomalidomide, can simultaneously interact with CRBN and some otherproteins. In doing so, CRBN may be exploited for target proteindegradation, such as IKZF1 and IKZF3. This is thought to account for theanti-myeloma effects of thalidomide and related compounds.

SUMMARY OF THE DISCLOSURE

In some embodiments, provided herein are compounds of Formula (I),stereoisomer or a mixture of stereoisomers, or a pharmaceuticallyacceptable salt, or hydrate thereof:

wherein:

R¹ is selected from H, C₁-C₆ acyl, or C₁-C₆ alkyl, each of which issubstituted with 0, 1, 2, or 3 R⁶;

R² and R³ are each independently selected from H, C₁-C₃ alkyl, or C₁-C₃haloalkyl, each of which is substituted with 0, 1, 2, or 3 R⁶;

each R⁴ is independently selected from H, hydroxyl, C₁-C₃ alkyl, C₁-C₃alkoxyl, or C₁-C₃ haloalkyl, each of which is substituted with 0, 1, 2,or 3 R⁶, or two R⁴ groups are taken together to form an oxo;

R⁵ is selected from hydrogen, halogen, hydroxy, C₁-C₃ alkyl, C₁-C₃alkoxy, C₁-C₃ haloalkyl, —N(R⁷)₂, and —CN, each of which is substitutedwith 0, 1, 2, or 3 R⁶;

X¹ and X² are each independently selected from H, halogen, cyano, C₁-C₆alkyl, C₁-C₆ alkoxyl, or C₁-C₆ haloalkyl each of which is substitutedwith 0, 1, 2, or 3 R⁶;

X³ and X⁴ are each independently selected from H or halo;

L is a linker of 1 to 22 carbon atoms in length, wherein one or morecarbon atoms are each optionally and independently replaced by a groupselected from C(O), O, NR⁷, S, C₂-alkenyl, C₂-alkynyl, cycloalkyl, aryl,heterocycle, and heteroaryl, each of which is substituted with 0, 1, 2,or 3 R⁶;

each R⁶ is independently selected from C₁-C₆ alkyl, halo, cyano, andhydroxy,

each R⁷ is independently selected from hydrogen, C₁-C₆ alkyl, and acyl,each of which is substituted with 0, 1, 2, or 3 R⁶, or two R⁷ groups aretaken together to form a 3- to 6-membered heterocycle or heteroaryl.

In some embodiments, the compound of Formula (I) may encompass both thecis- and trans-isomers. In some embodiments, the compound of Formula (I)may be a mixture of cis- and trans-isomers. In some embodiments, thecompound of Formula (I) may be cis-isomer.

In some embodiments, the compound of Formula (I) may encompass bothstereoisomes and a mixture of stereoisomers. In some embodiments, thecompound of Formula (I) is stereoisomer. In some embodiments, thecompound of Formula (I) may encompass both racemic isomers andenantiomeric isomers.

In some embodiments, provided herein is the compound of Formula (I)*:

Also provided herein is a method of treating cancer in a subject in needthereof, comprising administering to said subject an effective amount ofa compound disclosed herein. In some embodiments, the cancer is selectedfrom breast cancer, lung cancer, ovarian cancer, endometrial cancer,prostate cancer, and esophageal cancer.

BRIEF DESCRIPTION OF THE FIGURES

The foregoing summary, as well as the following detailed description ofthe disclosure, will be better understood when read in conjunction withthe appended drawings. For the purpose of illustrating the presentdisclosure, the attached drawings illustrate some, but not all,alternative embodiments. It should be understood, however, that thedisclosure is not limited to the precise arrangements andinstrumentalities shown. These figures, which are incorporated into andconstitute part of the specification, assist in explaining theprinciples of the disclosures.

FIGS. 1A to 1D illustrate the ERα degradative activity of exemplaryCompounds 85, 60, 32 and 52 of the present disclosure in a T47D cellline 6 hours after administration.

FIGS. 2A and 2B illustrate the ERα degradative activity of exemplaryCompounds 87 and 84 of the present disclosure in a T47D cell line 6hours after administration.

FIGS. 3A and 3B illustrate the ERα degradative activity of exemplaryCompounds 86 and 33 of the present disclosure in a MCF7 cell line 6hours after administration.

FIGS. 4A and 4B illustrate the ERα degradative activity of exemplaryCompounds 86 and 33 of the present disclosure in a T47D cell line 6hours after administration.

FIGS. 5A and 5B illustrate the ERα degradative activity of exemplaryCompounds 86 and 33 of the present disclosure in a CAMA-1 cell line 6hours after administration.

FIGS. 6A, 6B and 6C illustrate the ERα degradative activity of exemplaryCompounds 41, 42 and 63 of the present disclosure in a T47D cell line 6hours after administration.

FIGS. 7A, 7B, 7C and 7D illustrate the ERα degradative activity ofexemplary Compounds 89, 56, 90 and 74 of the present disclosure in aT47D cell line 6 hours after administration.

DETAILED DESCRIPTION Definitions

As used herein, “cancer” refers to diseases, disorders, and conditionsthat involve abnormal cell growth with the potential to invade or spreadto other parts of the body. Exemplary cancers, include, but are notlimited to, breast cancer, lung cancer, ovarian cancer, endometrialcancer, prostate cancer, and esophageal cancer.

“Subject” refers to an animal, such as a mammal, that has been or willbe the object of treatment, observation, or experiment. The methodsdescribed herein may be useful for both human therapy and veterinaryapplications. In one embodiment, the subject is a human.

As used herein, “treatment” or “treating” refers to an amelioration of adisease or disorder, or at least one discernible symptom thereof. Inanother embodiment, “treatment” or “treating” refers to an ameliorationof at least one measurable physical parameter, not necessarilydiscernible by the patient. In yet another embodiment, “treatment” or“treating” refers to inhibiting the progression of a disease ordisorder, either physically, e.g., stabilization of a discerniblesymptom, physiologically, e.g., stabilization of a physical parameter,or both. In yet another embodiment, “treatment” or “treating” refers todelaying the onset of a disease or disorder. For example, treating acholesterol disorder may comprise decreasing blood cholesterol levels.

As used herein, “prevention” or “preventing” refers to a reduction ofthe risk of acquiring a given disease or disorder.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CN isattached through the carbon atom.

By “optional” or “optionally” it is meant that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where the event or circumstance occursand instances in which is does not. For example, “optionally substitutedaryl” encompasses both “aryl” and “substituted aryl” as defined below.It will be understood by those skilled in the art, with respect to anygroup containing one or more substituents, that such groups are notintended to introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible and/or inherentlyunstable.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example, “C₁-C₆ alkyl” is intendedto encompass C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The term “acyl” as used herein refers to R—C(O)— groups such as, but notlimited to, (alkyl)-C(O)—, (alkenyl)-C(O)—, (alkynyl)-C(O)—,(aryl)-C(O)—, (cycloalkyl)-C(O)—, (heteroaryl)-C(O)—, and(heterocyclyl)-C(O)—, wherein the group is attached to the parentmolecular structure through the carbonyl functionality. In someembodiments, it is a C₁₋₁₀ acyl radical which refers to the total numberof chain or ring atoms of the, for example, alkyl, alkenyl, alkynyl,aryl, cycloalkyl, or heteroaryl, portion plus the carbonyl carbon ofacyl. For example, a C₄-acyl has three other ring or chain atoms pluscarbonyl.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond, suchas a straight or branched group of 2-8 carbon atoms, referred to hereinas (C₂—C)alkenyl. Exemplary alkenyl groups include, but are not limitedto, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl,hexadienyl, 2-ethyhexenyl, 2-propyl-2-butenyl, and4-(2-methyl-3-butene)-pentenyl.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-8 carbonatoms, referred to herein as (C₁-C₈)alkyl. Exemplary alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, andoctyl. In some embodiments, “alkyl” is a straight-chain hydrocarbon. Insome embodiments, “alkyl” is a branched hydrocarbon.

The term “alkynyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond, suchas a straight or branched group of 2-8 carbon atoms, referred to hereinas (C₂-C₈)alkynyl. Exemplary alkynyl groups include, but are not limitedto, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl,4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.

The term “aryl” as used herein refers to a mono-, bi-, or othermulti-carbocyclic, aromatic ring system with 5 to 14 ring atoms. Thearyl group can optionally be fused to one or more rings selected fromaryls, cycloalkyls, heteroaryls, and heterocyclyls. The aryl groups ofthis present disclosure can be substituted with groups selected fromalkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.Exemplary aryl groups include, but are not limited to, phenyl, tolyl,anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well asbenzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.Exemplary aryl groups also include but are not limited to a monocyclicaromatic ring system, wherein the ring comprises 6 carbon atoms,referred to herein as “Ce-aryl.”

The term “cyano” as used herein refers to —CN.

The term “cycloalkyl” as used herein refers to a saturated orunsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of3-16 carbons, or 3-8 carbons, referred to herein as “(C₃-C₈)cycloalkyl,”derived from a cycloalkane. Exemplary cycloalkyl groups include, but arenot limited to, cyclohexanes, cyclohexenes, cyclopentanes, andcyclopentenes. Cycloalkyl groups may be substituted with alkoxy,aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.Cycloalkyl groups can be fused to other cycloalkyl (saturated orpartially unsaturated), aryl, or heterocyclyl groups, to form a bicycle,tetracycle, etc. The term “cycloalkyl” also includes bridged andspiro-fused cyclic structures which may or may not contain heteroatoms.

The terms “halo” or “halogen” as used herein refer to —F, —Cl, —Br,and/or —I.

The term “heteroaryl” as used herein refers to a mono-, bi-, ormulti-cyclic, aromatic ring system containing one or more heteroatoms,for example 1-3 heteroatoms, such as nitrogen, oxygen, and sulfur.Heteroaryls can be substituted with one or more substituents includingalkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.Heteroaryls can also be fused to non-aromatic rings. Illustrativeexamples of heteroaryl groups include, but are not limited to,pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl,pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl,pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl,phenyl, isoxazolyl, and oxazolyl. Exemplary heteroaryl groups include,but are not limited to, a monocyclic aromatic ring, wherein the ringcomprises 2-5 carbon atoms and 1-3 heteroatoms, referred to herein as“(C₂-C₅)heteroaryl.”

The terms “heterocycle,” “heterocyclyl,” or “heterocyclic” as usedherein each refer to a saturated or unsaturated 3- to 18-membered ringcontaining one, two, three, or four heteroatoms independently selectedfrom nitrogen, oxygen, phosphorus, and sulfur. Heterocycles can bearomatic (heteroaryls) or non-aromatic. Heterocycles can be substitutedwith one or more substituents including alkoxy, aryloxy, alkyl, alkenyl,alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl,sulfonyl, sulfonic acid, sulfonamide and thioketone. Heterocycles alsoinclude bicyclic, tricyclic, and tetracyclic groups in which any of theabove heterocyclic rings is fused to one or two rings independentlyselected from aryls, cycloalkyls, and heterocycles. Exemplaryheterocycles include acridinyl, benzimidazolyl, benzofuryl,benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl,dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl,dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl,imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl,isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl,oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl,pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl,pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl,quinoxaloyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl,tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl,thienyl, thiomorpholinyl, thiopyranyl, and triazolyl.

The terms “hydroxy” and “hydroxyl” as used herein refer to —OH.

The term “pharmaceutically acceptable carrier” as used herein refers toany and all solvents, dispersion media, coatings, isotonic andabsorption delaying agents, and the like, that are compatible withpharmaceutical administration. The use of such media and agents forpharmaceutically active substances is well known in the art. Thecompositions may also contain other active compounds providingsupplemental, additional, or enhanced therapeutic functions.

The term “pharmaceutically acceptable composition” as used herein refersto a composition comprising at least one compound as disclosed hereinformulated together with one or more pharmaceutically acceptablecarriers.

The term “pharmaceutically acceptable prodrugs” as used hereinrepresents those prodrugs of the compounds of the present disclosurethat are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, commensurate with a reasonablebenefit/risk ratio, and effective for their intended use, as well as thezwitterionic forms, where possible, of the compounds of the presentdisclosure. A discussion is provided in Higuchi et al., “Prodrugs asNovel Delivery Systems,” ACS Symposium Series, Vol. 14, and in Roche, E.B., ed. Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

The term “pharmaceutically acceptable salt(s)” refers to salts of acidicor basic groups that may be present in compounds used in the presentcompositions. Compounds included in the present compositions that arebasic in nature are capable of forming a wide variety of salts withvarious inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including but notlimited to sulfate, citrate, matate, acetate, oxalate, chloride,bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate,isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate,tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds includedin the present compositions that include an amino moiety may formpharmaceutically acceptable salts with various amino acids, in additionto the acids mentioned above. Compounds included in the presentcompositions, that are acidic in nature are capable of forming basesalts with various pharmacologically acceptable cations. Examples ofsuch salts include alkali metal or alkaline earth metal salts and,particularly, calcium, magnesium, sodium, lithium, zinc, potassium, andiron salts.

Chemical names were generated using PerkinElmer ChemDraw® Professional,version 17.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “S,” depending on the configuration of substituentsaround the stereogenic carbon atom. The present disclosure encompassesvarious stereoisomers of these compounds and mixtures thereof.Stereoisomers include enantiomers and diastereomers. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly. In some embodiments, an enantiomer orstereoisomer may be provided substantially free of the correspondingenantiomer.

In some embodiments, the compound is a racemic mixture of (S)- and(R)-isomers. In other embodiments, provided herein is a mixture ofcompounds wherein individual compounds of the mixture existpredominately in an (S)- or (R)-isomeric configuration. For example, thecompound mixture has an (S)-enantiomeric excess of greater than about55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%,about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about99.5%, or more. In other embodiments, the compound mixture has an(S)-enantiomeric excess of greater than about 55% to about 99.5%,greater than about 60% to about 99.5%, greater than about 65% to about99.5%, greater than about 70% to about 99.5%, greater than about 75% toabout 99.5%, greater than about 80% to about 99.5%, greater than about85% to about 99.5%, greater than about 90% to about 99.5%, greater thanabout 95% to about 99.5%, greater than about 96% to about 99.5%, greaterthan about 97% to about 99.5%, greater than about 98% to greater thanabout 99.5%, greater than about 99% to about 99.5%, or more. In otherembodiments, the compound mixture has an (R)-enantiomeric purity ofgreater than about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about98%, about 99%, about 99.5% or more. In some other embodiments, thecompound mixture has an (R)-enantiomeric excess of greater than about55% to about 99.5%, greater than about 60% to about 99.5%, greater thanabout 65% to about 99.5%, greater than about 70% to about 99.5%, greaterthan about 75% to about 99.5%, greater than about 80% to about 99.5%,greater than about 85% to about 99.5%, greater than about 90% to about99.5%, greater than about 95% to about 99.5%, greater than about 96% toabout 99.5%, greater than about 97% to about 99.5%, greater than about98% to greater than about 99.5%, greater than about 99% to about 99.5%or more.

Individual stereoisomers of compounds of the present disclosure can beprepared synthetically from commercially available starting materialsthat contain asymmetric or stereogenic centers, or by preparation ofracemic mixtures followed by resolution methods well known to those ofordinary skill in the art. These methods of resolution are exemplifiedby: (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary; (2) salt formation employing an opticallyactive resolving agent; or (3) direct separation of the mixture ofoptical enantiomers on chiral chromatographic columns. Stereoisomericmixtures can also be resolved into their component stereoisomers bywell-known methods, such as chiral-phase gas chromatography,chiral-phase high performance liquid chromatography, crystallizing thecompound as a chiral salt complex, or crystallizing the compound in achiral solvent. Stereoisomers can also be obtained fromstereomerically-pure intermediates, reagents, and catalysts bywell-known asymmetric synthetic methods.

Geometric isomers can also exist in the compounds of the presentdisclosure. The present disclosure encompasses the various geometricisomers and mixtures thereof resulting from the arrangement ofsubstituents around a carbon-carbon double bond or arrangement ofsubstituents around a carbocyclic ring. Substituents around acarbon-carbon double bond are designated as being in the “Z” or “E”configuration wherein the terms “Z” and “E” are used in accordance withIUPAC standards. Unless otherwise specified, structures depicting doublebonds encompass both the E and Z isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “ci” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangements of substituentsaround a carbocyclic ring are designated as “ci” or “trans.” The term“ci” represents substituents on the same side of the plane of the ringand the term “trans” represents substituents on opposite sides of theplane of the ring. Mixtures of compounds wherein the substituents aredisposed on both the same and opposite sides of plane of the ring aredesignated “cis/trans.”

The compounds disclosed herein may exist as tautomers and bothtautomeric forms are intended to be encompassed by the scope of thepresent disclosure, even though only one tautomeric structure isdepicted.

Additionally, unless otherwise stated, structures described herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures except for the replacement of hydrogen by deuterium(²H) or tritium (³H), or the replacement of a carbon by a ¹³C- or¹⁴C-carbon atom are within the scope of this disclosure. Such compoundsmay be useful as, for example, analytical tools, probes in biologicalassays, or therapeutic agents.

Compounds

In some embodiments, provided herein are compounds of Formula (I), astereoisomer or a mixture of stereoisomers, a pharmaceuticallyacceptable salt, or hydrate thereof:

wherein:

R¹ is selected from H, C₁-C₆ acyl, or C₁-C₆ alkyl, each of which issubstituted with 0, 1, 2, or 3 R⁶;

R² and R³ are each independently selected from H, C₁-C3 alkyl, or C₁-C₃haloalkyl, each of which is substituted with 0, 1, 2, or 3 R⁶;

each R⁴ is independently selected from H, hydroxyl, C₁-C₃ alkyl, C₁-C₃alkoxyl, or C₁-C₃ haloalkyl, each of which is substituted with 0, 1, 2,or 3 R⁶, or two R⁴ groups are taken together to form an oxo;

R⁵ is selected from hydrogen, halogen, hydroxy, C₁-C₃ alkyl, C₁-C₃alkoxy, C₁-C₃ haloalkyl, —N(R⁷)₂, and —CN, each of which is substitutedwith 0, 1, 2, or 3 R⁶;

X¹ and X² are each independently selected from H, halogen, cyano, C₁-C₆alkyl, C₁-C₆ alkoxyl, or C₁—C haloalkyl each of which is substitutedwith 0, 1, 2, or 3 R⁶;

X³ and X⁴ are each independently selected from H or halo;

L is a linker of 1 to 22 carbon atoms in length, wherein one or morecarbon atoms are each optionally and independently replaced by a groupselected from C(O), O, NR⁷, S, C₂-alkenyl, C₂-alkynyl, cycloalkyl, aryl,heterocycle, and heteroaryl, each of which is substituted with 0, 1, 2,or 3 R⁶;

each R⁶ is independently selected from C₁-C₆ alkyl, halo, cyano, andhydroxy,

each R⁷ is independently selected from hydrogen, C₁-C₆ alkyl, and acyl,each of which is substituted with 0, 1, 2, or 3 R⁶, or two R⁷ groups aretaken together to form a 3- to 6-membered heterocycle or heteroaryl.

In some embodiments, R¹ is selected from H, or C₁-C₆ alkyl, each ofwhich is substituted with 0, 1, 2, or 3 R⁶. In some embodiments, R¹ maybe selected from H or methyl, each of which is substituted with 0, 1, 2,or 3 R⁶. In some embodiments, R¹ may each be independently H or methyl.

In some embodiments, R¹ may be H. In some embodiments, R¹ may be methyl.

In some embodiments, R² and R³ are each independently selected from H,C₁-C₃ alkyl, or C₁-C₃ haloalkyl, each of which is substituted with 0, 1,2, or 3 R⁶. In some embodiments, R² and R³ are each independentlyselected from H and methyl, each of which is substituted with 0, 1, 2,or 3 R⁶. In some embodiments, R² and R³ are each independently selectedfrom H and methyl.

In some embodiments, R² may be H and R³ may be H. In some embodiments,R² may be H and R³ may be methyl. In some embodiments, R² may be methyland R³ may be H. In some embodiments, R² may be methyl and R³ may bemethyl.

In some embodiments, each R⁴ is independently selected from H, hydroxyl,C₁-C₃ alkyl, C₁-C₃ alkoxyl, or C₁-C₃ haloalkyl, each of which issubstituted with 0, 1, 2, or 3 R⁶, or two R⁴ groups are taken togetherto form an oxo. In some embodiments, each R⁴ is independently selectedfrom H, hydroxyl, C₁-C₃ alkyl, C₁-C₃ alkoxyl, or C₁-C₃ haloalkyl, or twoR⁴ groups are taken together to form an oxo. In some embodiments, R⁴ isH. In some embodiments, two R⁴ groups are taken together to form an oxo.

In some embodiments, R⁵ is selected from hydrogen, halogen, hydroxy,C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃ haloalkyl, —N(R⁷)₂, and —CN, each ofwhich is substituted with 0, 1, 2, or 3 R⁶. In some embodiments, R⁵ isselected from hydrogen, halogen, hydroxy, C₁-C₃ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, —N(R⁷)₂, and —CN. In some embodiments, R⁵ is selectedfrom halogen. In some embodiments, R⁵ may be F.

In some embodiments, X¹ and X² are each independently selected from H,halogen, cyano, C₁-C₆ alkyl, C₁-C₆ alkoxyl, or C₁-C₆ haloalkyl, each ofwhich is substituted with 0, 1, 2, or 3 R⁶. In some embodiments, X¹ andX² are each independently selected from H, halogen, cyano, C₁-C₆ alkyl,C₁-C₆ alkoxyl, or C₁-C₆ haloalkyl. In some embodiments, X¹ and X² areeach independently selected from H, F, CN, methyl, methoxy,trifluoromethyl.

In some embodiments, X¹ is H and X² is H. In some embodiments, X¹ is Fand X² is F. In some embodiments, X¹ is H and X² is methyl. In someembodiments, X¹ is methyl and X² is H. In some embodiments, X¹ is H andX² is F. In some embodiments, X¹ is F and X² is H. In some embodiments,X¹ is H and X² is methoxy. In some embodiments, X¹ is methoxy and X² isH. In some embodiments, X¹ is F and X² is methyl. In some embodiments,X¹ is methyl and X² is F. In some embodiments, X¹ is F and X² ismethoxy. In some embodiments, X¹ is methoxy and X² is F. In someembodiments, X¹ is F and X² is trifluoromethyl. In some embodiments, X¹is trifluoromethyl and X² is F.

In some embodiments, X³ and X⁴ are each independently selected from H orhalo. In some embodiments, X³ and X⁴ are each independently selectedfrom H or F.

In some embodiments, X³ is H and X⁴ is H. In some embodiments, X³ is Fand X⁴ is F. In some embodiments, X³ is H and X⁴ is F. In someembodiments, X³ is F and X⁴ is H.

In some embodiments, L may be linker of 1 to 22 carbon atoms in length,wherein one or more carbon atoms are each optionally and independentlyreplaced by a group selected from C(O), O, NR⁴, S, C₂-alkenyl,C₂-alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of whichis independently substituted with 0, 1, 2, or 3 R⁵. In some embodiments,L may be linker of 1 to 20 carbon atoms in length, wherein one or morecarbon atoms are each optionally and independently replaced by a groupselected from C(O), O, NR⁴, S, C₂-alkenyl, C₂-alkynyl, cycloalkyl, aryl,heterocycle, and heteroaryl, each of which is independently substitutedwith 0, 1, 2, or 3 R⁵. In some embodiments, L may be linker of 1 to 18carbon atoms in length, wherein one or more carbon atoms are eachoptionally and independently replaced by a group selected from C(O), O,NR⁴, S, C₂-alkenyl, C₂-alkynyl, cycloalkyl, aryl, heterocycle, andheteroaryl, each of which is independently substituted with 0, 1, 2, or3 R⁵. In some embodiments, L may be linker of 1 to 16 carbon atoms inlength, wherein one or more carbon atoms are each optionally andindependently replaced by a group selected from C(O), O, NR⁴, S,C₂-alkenyl, C₂-alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl,each of which is independently substituted with 0, 1, 2, or 3 R⁵. Insome embodiments, L may be a linker of 1 to 14 carbon atoms in length,wherein one or more carbon atoms are each optionally and independentlyreplaced by a group selected from C(O), O, NR⁴, S, C₂-alkenyl,C₂-alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of whichis independently substituted with 0, 1, 2, or 3 R⁵. In some embodiments,L may be a linker of 1 to 12 carbon atoms in length, wherein one or morecarbon atoms are each optionally and independently replaced by a groupselected from C(O), O, NR⁴, S, C₂-alkenyl, C₂-alkynyl, cycloalkyl, aryl,heterocycle, and heteroaryl, each of which is independently substitutedwith 0, 1, 2, or 3 R⁵. In some embodiments, L may be a linker of 1 to 10carbon atoms in length, wherein one or more carbon atoms are eachoptionally and independently replaced by a group selected from C(O), O,NR⁴, S, C₂-alkenyl, C₂-alkynyl, cycloalkyl, aryl, heterocycle, andheteroaryl, each of which is independently substituted with 0, 1, 2, or3 R⁵.

In some embodiments, L may be a linker of 1 to 8 carbon atoms in length,wherein one or more carbon atoms are each optionally and independentlyreplaced by a group selected from C(O), O, NR⁴, S, C₂-alkenyl,C₂-alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of whichis independently substituted with 0, 1, 2, or 3 R⁵. In some embodiments,L may be a linker of 1 to 6 carbon atoms in length, wherein one or morecarbon atoms are each optionally and independently replaced by a groupselected from C(O), O, NR⁴, S, C₂-alkenyl, C₂-alkynyl, cycloalkyl, aryl,heterocycle, and heteroaryl, each of which is independently substitutedwith 0, 1, 2, or 3 R⁵. In some embodiments, L may be linker of 1 to 4carbon atoms in length, wherein one or more carbon atoms are eachoptionally and independently replaced by a group selected from C(O), O,NR⁴, S, C₂-alkenyl, C₂-alkynyl, cycloalkyl, aryl, heterocycle, andheteroaryl, each of which is independently substituted with 0, 1, 2, or3 R⁵.

In some embodiments, L may be a linker wherein two carbon atoms are eachindependently replaced by a heterocycle, each of which is independentlysubstituted with 0, 1, 2, or 3 R⁵. In some embodiments, L may be alinker wherein one carbon atom is replaced by a heterocycle and onecarbon atom is replaced by a cycloalkyl, each of which is independentlysubstituted with 0, 1, 2, or 3 R⁵. In some embodiments, L may be alinker wherein more than one carbon atoms are each independentlyreplaced by a group selected from C(O), O, NR⁴, S, C₂-alkenyl,C₂-alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of whichis substituted with 0, 1, 2, or 3 R⁵. In some embodiments, L may be alinker wherein more than one carbon atoms are each independentlyreplaced by a group selected from C(O), O, and NR⁴, each of which issubstituted with 0, 1, 2, or 3 R⁵.

In some embodiments, L may be

In some embodiments, L may be

In some embodiments, L may be

In some embodiments, L may be

In some embodiments, L may be

In some embodiments, L may be

In some embodiments, L may be

In some embodiments, L may be

In some embodiments, L may be

In some embodiments, L may be

In some embodiments, L may be

In some embodiments, the compound of formula (I) is cis-isomer.

In some embodiments, the compound of formula (I) is a stereoisomer.

In some embodiments, provided herein is a compound of formula (I)*:

In some embodiments, provided herein is a compound, or pharmaceuticallyacceptable salt thereof, chosen from the compounds listed in Table 1.

TABLE 1 Exemplary Compound of the Present Disclosure Cpd # ChemicalStructure IUPAC Name 1

cis-3-(5-(2-(2-(2-(4-(7-hydroxy-3- phenylchroman-4-yl)phenoxy)ethoxy)ethoxy)ethoxy)-1- oxoisoindolin-2-yl)piperidine-2,6-dione 2

cis-3-(5-(2-(2-((2-(4-(7-hydroxy-3- phenylchroman-4-yl)phenoxy)ethyl)(methyl)amino)ethoxy) ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3

cis-3-(5-(2-(4-(2-(4-(7-hydroxy-3- phenylchroman-4-yl)phenoxy)ethyl)piperazin-1-yl)ethoxy)-1- oxoisoindolin-2-yl)piperidine-2,6- dione4

cis-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-N-(2-(4-(7- hydroxy-3-phenylchroman-4-yl)phenoxy)ethyl)-N- methylpentanamide 5

cis-3-(5-((5-(4-(4-(7-hydroxy-3- phenylchroman-4-yl)phenyl)piperazin-1-yl)pentyl)oxy)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 6

cis-3-(5-(6-(4-(4-(7-hydroxy-3- phenylchroman-4-yl)phenyl)piperazin-1-yl)hex-1-yn-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 7

cis-3-(4-(6-(4-(4-(7-hydroxy-3- phenylchroman-4-yl)phenyl)piperazin-1-yl)hex-1-yn-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 8

cis-2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-(4-(7-hydroxy-3-phenylchroman-4- yl)phenyl)piperazin-1-yl)pentyl)amino)isoindoline-1,3-dione 9

cis-3-(5-(3-(1-(2-(4-(7-hydroxy-3- phenylchroman-4-yl)phenoxy)ethyl)azetidin-3-yl)propoxy)- 1-oxoisoindolin-2-yl)piperidine-2,6- dione10

cis-3-(5-(4-(1-(2-(4-(7-hydroxy-3- phenylchroman-4-yl)phenoxy)ethyl)azetidin-3-yl)but-1-yn- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 11

cis-3-(4-(4-(1-(2-(4-(7-hydroxy-3- phenylchroman-4-yl)phenoxy)ethyl)azetidin-3-yl)but-1-yn- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 12

cis-2-(2,6-dioxopiperidin-3-yl)-5-(4- (5-(4-(7-hydroxy-3-phenylchroman-4-yl)phenoxy)pentyl)piperazin-1- yl)isoindoline-1,3-dione 13

cis-3-(5-(4-(5-(4-(7-hydroxy-3- phenylchroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione 14

cis-3-(5-(4-(5-(2-fluoro-4-(3-(4-fluoro- 3-(trifluoromethyl)phenyl)-7-hydroxychroman-4-yl) phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione 15

cis-3-(5-(4-(5-(2-fluoro-4-(3-(4- fluorophenyl)-7-hydroxychroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione 16

cis-3-(5-(4-(5-(2-fluoro-4-(3-(4-fluoro-3-methylphenyl)-7-hydroxychroman- 4-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione 17

cis-3-(5-(4-(5-(2-fluoro-4-(7-hydroxy- 3-(m-tolyl)chroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione 18

cis-3-(5-(4-(5-(2-fluoro-4-(3-(4-fluoro-2-methylphenyl)-7-hydroxychroman- 4-yl)henoxy)pentypiperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione 19

cis-3-(5-(4-(5-(4-(3-(3,4- difluorophenyl)-7- hydroxychroman-4-yl)-2-fluorophenoxy)pentyl)piperazin- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 20

cis-3-(5-(4-(5-(4-(3-(4-fluoro-3- (trifluoromethyl)phenyl)-7-hydroxychroman-4-yl) phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione 21

cis-3-(5-(4-(5-(4-(3-(4-fluoro-3- methoxyphenyl)-7-hydroxychroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione 22

cis-3-(5-(4-(5-(4-(3-(4-fluoro-2- (trifluoromethyl)phenyl)-7-hydroxychroman-4-yl) phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione 23

cis-3-(5-(4-(5-(4-(3-(4-fluoro-3- methylphenyl)-7-hydroxychroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione 24

cis-3-(5-(4-(5-(4-(7-hydroxy-3-(o- tolyl)chroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione 25

cis-3-(5-(4-(4-(4-(7-hydroxy-3- phenylchroman-4-yl)phenoxy)butyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione 26

cis-3-(5-(4-(5-(4-(7-hydroxy-2,2- dimethyl-3-phenylchroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione 27

cis-3-(5-(4-(5-(4-(7-methoxy-3- phenylchroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione 28

3-(5-(4-(5-(4-((2R,3S,4R)-7-hydroxy- 2-methyl-3-phenylchroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione 29

3-(5-(4-(5-(4-((2S,3S,4R)-7-hydroxy- 2-methyl-3-phenylchroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione 30

3-(5-(4-(5-(4-((2R,3R,4S)-7-hydroxy- 2-methyl-3-phenylchroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione 31

3-(5-(4-(5-(4-((2S,3R,4S)-7-hydroxy- 2-methyl-3-phenylchroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione 32

cis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione 33

(S)-3-(5-(4-((1-(4-((3S,4R)-7- hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 34

(S)-3-(5-(4-((1-(4-((3R,4S)-7- hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 35

cis-3-(5-(4-((1-(4-(7-hydroxy-3- phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 36

cis-2-(2,6-dioxopiperidin-3-yl)-5-(4- ((1-(4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl) methyl)piperazin-1-yl)isoindoline-1,3- dione37

cis-2-(2,6-dioxopiperidin-3-yl)-5-(4- (2-(1-(4-(7-hydroxy-3-phenylchroman-4-yl)phenyl) piperidin-4-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione 38

cis-2-(2,6-dioxopiperidin-3-yl)-5- fluoro-6-4-((1-(4-(7-hydroxy-3-phenylchroman-4- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline- 1,3-dione 39

cis-(S)-3-(6-fluoro-5-(4-((1-(4-(7- hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 40

cis-(S)-3-(6-fluoro-5-(4-((1-(2- fluoro-4-(7-hydroxy-3-phenylchroman-4-yl)phenyl) piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione 41

(S)-3-(6-fluoro-5-(4-((1-(2-fluoro- 4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl) piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl) piperidine-2,6-dione 42

(S)-3-(6-fluoro-5-(4-((1-(4-((3S,4R)- 7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 43

(S)-3-(6-fluoro-5-(4-((1-(4-((3R,4S)- 7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 44

cis-(S)-3-(5-(4-(2-(1-(4-(7-hydroxy- 3-phenylchroman-4-yl)phenyl)piperidin-4-yl)ethyl)piperazin- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 45

(S)-3-(5-(4-((1-(2-fluoro-4-((3R,4S)- 7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 46

(S)-3-(5-(4-((1-(2-fluoro-4-((3S,4R)- 7-hydroxy-2,2-dimethyl-3-phenylchroman-4-yl)phenyl) piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione 47

(S)-3-(5-(4-((1-(2-fluoro-4- ((2R,3S,4R)-7-hydroxy-2-methyl-3-phenylchroman-4-yl)phenyl) piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl) piperidine-2,6-dione 48

(S)-3-(5-(4-((1-(2-fluoro-4- ((2S,3S,4R)-7-hydroxy-2-methyl-3-phenylchroman-4-yl)phenyl) piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl) piperidine-2,6-dione 49

(S)-3-(5-(4-((1-(2-fluoro-4-((3S,4R)- 7-methoxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 50

cis-(S)-3-(5-(4-((1-(2-fluoro-4-(3-(4- fluorophenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 51

cis-(S)-3-(5-(4-((1-(4-(3-(4- fluorophenyl)-7-hydroxychroman-4-yl)phenyl) piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 52

cis-(S)-3-(5-(4-((1-(2-fluoro-4-(7- hydroxy-3-(m-tolyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 53

cis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3- (m-tolyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 54

cis-(S)-3-(5-(4-((1-(2-fluoro-4-(7- hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione 55

(S)-3-(5-(4-((1-(2-fluoro-4-((3S,4R)- 7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl) methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione 56

cis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3- (3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 57

cis-3-(5-(4-((1-(4-(7-hydroxy-3-(3- methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 58

cis-(S)-3-(5-(4-((1-(2-fluoro-4-(7- hydroxy-3-(3-methoxyphenyl)-2,2-dimethylchroman-4-yl)phenyl) piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 59

cis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3- (3-methoxyphenyl)-2,2-dimethylchroman-4-yl)phenyl) piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl) piperidine-2,6-dione 60

cis-(S)-3-(5-(4-((1-(2-fluoro-4-(3-(4- fluoro-3-methylphenyl)-7-hydroxychroman-4-yl)phenyl) piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 61

cis-(S)-3-(5-(4-((1-(2-fluoro-4-(3-(4- fluoro-3-methoxyphenyl)-7-hydroxychroman-4-yl)phenyl) piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 62

cis-(S)-3-(5-(4-((1-(4-(3-(4-fluoro-3- methylphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 63

cis-(S)-3-(5-(4-((1-(4-(3-(4-fluoro-3- methoxyphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 64

cis-(S)-3-(5-(4-((1-(2-fluoro-4-(3-(4- fluoro-2-methylphenyl)-7-hydroxychroman-4-yl)phenyl) piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 65

cis-(S)-3-(5-(4-((1-(4-(3-(4-fluoro-2- methylphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 66

cis-(S)-3-(5-(4-((1-(4-((2R)-7- hydroxy-3-(3-methoxyphenyl)-2-methylchroman-4-yl)phenyl) piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl) piperidine-2,6-dione 67

cis-(S)-3-(5-(4-((1-(4-((2S)-7- hydroxy-3-(3-methoxyphenyl)-2-methylchroman-4-yl)phenyl) piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione 68

cis-3-(5-(3-(((1-(4-(7-hydroxy-3-(3- methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl) (methyl)amino)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 69

cis-3-(5-(3-(((1-(2-fluoro-4-(7- hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4- yl)methyl)(methyl)amino)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl) piperidine-2,6-dione 70

cis-3-(5-(3-(((1-(2-fluoro-4-(7- hydroxy-3-(m-tolyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl) (methyl)amino)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 71

cis-3-(5-(3-(((1-(4-(7-hydroxy-3- (m-tolyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)(methyl) amino)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione 72

cis-(S)-3-(6-fluoro-5-(4-((1-(2- fluoro-4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl) phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione 73

cis-2-(2,6-dioxopiperidin-3-yl)-5- fluoro-6-(4-((1-(2-fluoro-4-(7-hydroxy-3-(3-methoxyphenyl) chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl) isoindoline-1,3-dione 74

cis-(S)-3-(6-fluoro-5-(4-((1-(4-(7- hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione 75

cis-2-(2,6-dioxopiperidin-3-yl)-5- fluoro-6-(4-((1-(4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline- 1,3-dione 76

cis-(S)-3-(6-fluoro-5-(4-((1-(2- fluoro-4-(3-(4-fluoro-3-methylphenyl)-7-hydroxychroman- 4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 77

cis-(S)-3-(6-fluoro-5-(4-((1-(4-(3- (4-fluoro-3-methylphenyl)-7-hydroxychroman-4-yl)phenyl) piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 78

cis-(S)-3-(6-fluoro-5-(4-((1-(2-fluoro-4-(7-hydroxy-3-(m-tolyl)chroman-4- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione 79

cis-(S)-3-(6-fluoro-5-(4-((1-(4-(7- hydroxy-3-(m-tolyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 80

cis-(S)-3-(6-fluoro-5-(4-((1-(2- fluoro-4-(3-(4-fluoro-3-methoxyphenyl)-7-hydroxychroman- 4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione 81

cis-(S)-3-(5-(4-((1-(2,6-difluoro-4-(7- hydroxy-3-(m-tolyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 82

cis-(S)-3-(5-(4-((1-(2-fluoro-4-(7- methoxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 83

cis-2-(2,6-dioxopiperidin-3-yl)-5-(4- ((1-(2-fluoro-4-(7-methoxy-3-phenylchroman-4-yl)phenyl) piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione 84

cis-(S)-3-(5-(4-((1-(4-(3-(3,4- difluorophenyl)-7-hydroxychroman-4-yl)-2-fluorophenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione 85

cis-(S)-3-(5-(4-((1-(2-fluoro-4-(7- hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 86

(S)-3-(5-(4-((1-(2-fluoro-4-((3S,4R)- 7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 87

cis-2-(2,6-dioxopiperidin-3-yl)-5-(4- ((1-(2-fluoro-4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione 88

cis-(S)-3-(5-(4-((1-(2,6-difluoro-4- (7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione 89

cis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3- (4-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 90

cis-(S)-3-(6-fluoro-5-(4-((1-(4-(7- hydroxy-3-(4-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dionePharmaceutical Compositions

Pharmaceutical compositions of the present disclosure comprise at leastone compound of Formula (I), or tautomer, stereoisomer, pharmaceuticallyacceptable salt or hydrate thereof formulated together with one or morepharmaceutically acceptable carriers. These formulations include thosesuitable for oral, rectal, topical, buccal and parenteral (e.g.,subcutaneous, intramuscular, intradermal, or intravenous)administration. The most suitable form of administration in any givencase will depend on the degree and severity of the condition beingtreated and on the nature of the particular compound being used.

Formulations suitable for oral administration may be presented indiscrete units, such as capsules, cachets, lozenges, or tablets, eachcontaining a predetermined amount of a compound of the presentdisclosure as powder or granules; as a solution or a suspension in anaqueous or non-aqueous liquid; or as an oil-in-water or water-in-oilemulsion. As indicated, such formulations may be prepared by anysuitable method of pharmacy which includes the step of bringing intoassociation at least one compound of the present disclosure as theactive compound and a carrier or excipient (which may constitute one ormore accessory ingredients). The carrier must be acceptable in the senseof being compatible with the other ingredients of the formulation andmust not be deleterious to the recipient. The carrier may be a solid ora liquid, or both, and may be formulated with at least one compounddescribed herein as the active compound in a unit-dose formulation, forexample, a tablet, which may contain from about 0.05% to about 95% byweight of the at least one active compound. Other pharmacologicallyactive substances may also be present including other compounds. Theformulations of the present disclosure may be prepared by any of thewell-known techniques of pharmacy consisting essentially of admixing thecomponents.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. Liquid pharmacologicallyadministrable compositions can, for example, be prepared by, forexample, dissolving or dispersing, at least one active compound of thepresent disclosure as described herein and optional pharmaceuticaladjuvants in an excipient, such as, for example, water, saline, aqueousdextrose, glycerol, ethanol, and the like, to thereby form a solution orsuspension. In general, suitable formulations may be prepared byuniformly and intimately admixing the at least one active compound ofthe present disclosure with a liquid or finely divided solid carrier, orboth, and then, if necessary, shaping the product. For example, a tabletmay be prepared by compressing or molding a powder or granules of atleast one compound of the present disclosure, which may be optionallycombined with one or more accessory ingredients. Compressed tablets maybe prepared by compressing, in a suitable machine, at least one compoundof the present disclosure in a free-flowing form, such as a powder orgranules, which may be optionally mixed with a binder, lubricant, inertdiluent and/or surface active/dispersing agent(s). Molded tablets may bemade by molding, in a suitable machine, where the powdered form of atleast one compound of the present disclosure is moistened with an inertliquid diluent.

Formulations suitable for buccal (sub-lingual) administration includelozenges comprising at least one compound of the present disclosure in aflavored base, usually sucrose and acacia or tragacanth, and pastillescomprising the at least one compound in an inert base such as gelatinand glycerin or sucrose and acacia.

Formulations of the present disclosure suitable for parenteraladministration comprise sterile aqueous preparations of at least onecompound of Formula (I), or tautomers, stereoisomers, pharmaceuticallyacceptable salts, and hydrates thereof, which are approximately isotonicwith the blood of the intended recipient. These preparations areadministered intravenously, although administration may also be effectedby means of subcutaneous, intramuscular, or intradermal injection. Suchpreparations may conveniently be prepared by admixing at least onecompound described herein with water and rendering the resultingsolution sterile and isotonic with the blood. Injectable compositionsaccording to the present disclosure may contain from about 0.1 to about5% w/w of the active compound.

Formulations suitable for rectal administration are presented asunit-dose suppositories. These may be prepared by admixing at least onecompound as described herein with one or more conventional solidcarriers, for example, cocoa butter, and then shaping the resultingmixture.

Formulations suitable for topical application to the skin may take theform of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.Carriers and excipients which may be used include Vaseline, lanoline,polyethylene glycols, alcohols, and combinations of two or more thereof.The active compound (i.e., at least one compound of Formula (I), ortautomers, stereoisomers, pharmaceutically acceptable salts, andhydrates thereof) is generally present at a concentration of from about0.1% to about 15% w/w of the composition, for example, from about 0.5 toabout 2%.

The amount of active compound administered may be dependent on thesubject being treated, the subject's weight, the manner ofadministration and the judgment of the prescribing physician. Forexample, a dosing schedule may involve the daily or semi-dailyadministration of the encapsulated compound at a perceived dosage ofabout 1 μg to about 1000 mg. In another embodiment, intermittentadministration, such as on a monthly or yearly basis, of a dose of theencapsulated compound may be employed. Encapsulation facilitates accessto the site of action and allows the administration of the activeingredients simultaneously, in theory producing a synergistic effect. Inaccordance with standard dosing regimens, physicians will readilydetermine optimum dosages and will be able to readily modifyadministration to achieve such dosages.

A therapeutically effective amount of a compound or compositiondisclosed herein can be measured by the therapeutic effectiveness of thecompound. The dosages, however, may be varied depending upon therequirements of the patient, the severity of the condition beingtreated, and the compound being used. In one embodiment, thetherapeutically effective amount of a disclosed compound is sufficientto establish a maximal plasma concentration. Preliminary doses as, forexample, determined according to animal tests, and the scaling ofdosages for human administration is performed according to art-acceptedpractices.

Toxicity and therapeutic efficacy can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀.Compositions that exhibit large therapeutic indices are preferable.

Data obtained from the cell culture assays or animal studies can be usedin formulating a range of dosage for use in humans. Therapeuticallyeffective dosages achieved in one animal model may be converted for usein another animal, including humans, using conversion factors known inthe art (see, e.g., Freireich et al., Cancer Chemother. Reports50(4):219-244 (1966) and the following Table for Equivalent Surface AreaDosage Factors).

TABLE 2 Equivalent Surface Area Dosage Factors. To: Mouse Rat Monkey DogHuman From: (20 g) (150 g) (3.5 kg) (8 kg) (60 kg) Mouse  1 1/2 1/4 1/61/12 Rat  2 1 1/2 1/4 1/7 Monkey  4 2 1 3/5 1/3 Dog  6 4 3/5 1 1/2 Human12 7 3 2 1

The dosage of such compounds lies preferably within a range ofcirculating concentrations that include the ED₅₀ with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized.Generally, a therapeutically effective amount may vary with thesubject's age, condition, and gender, as well as the severity of themedical condition in the subject. The dosage may be determined by aphysician and adjusted, as necessary, to suit observed effects of thetreatment.

Methods of Treatment

In some embodiments, a compound of Formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt or hydrate thereof, isadministered to treat cancer in a subject in need thereof. In someembodiments, the cancer is chosen from breast cancer, lung cancer,ovarian cancer, endometrial cancer, prostate cancer, and esophagealcancer. In some embodiments, the cancer is breast cancer. In someembodiments, the cancer is lung cancer. In some embodiments, the canceris ovarian cancer. In some embodiments, the cancer is endometrialcancer. In some embodiments, the cancer is prostate cancer. In someembodiments, the cancer is esophageal cancer. In some embodiments, thecancer is positive for ERα. In some embodiments, a compound of Formula(I), or a tautomer, stereoisomer, pharmaceutically acceptable salt orhydrate thereof, is administered as a pharmaceutical composition. Insome embodiments, the subject has been previously treated withtamoxifen.

In some embodiments, provided herein is a use of a compound of Formula(I), or a tautomer, stereoisomer, pharmaceutically acceptable salt orhydrate thereof, in a therapeutic treatment. In some embodiments, thetherapeutic treatment is for the treatment of breast cancer, lungcancer, ovarian cancer, endometrial cancer, prostate cancer, andesophageal cancer. In some embodiments, the therapeutic treatment is forthe treatment of breast cancer. In some embodiments, the therapeutictreatment is for lung cancer. In some embodiments, the therapeutictreatment is for the treatment of ovarian cancer. In some embodiments,the therapeutic treatment is for the treatment of endometrial cancer. Insome embodiments, the therapeutic treatment is for the treatment ofprostate cancer. In some embodiments, the therapeutic treatment is forthe treatment of esophageal cancer. In some embodiments, the therapeutictreatment is for the treatment of estrogen-related diseases andconditions. In some embodiments, the therapeutic treatment is for thetreatment of infertility. In some embodiments, the therapeutic treatmentis for the treatment of ovulatory dysfunction. In some embodiments, thetherapeutic treatment is for the treatment of postmenopausalosteoporosis. In some embodiments, the therapeutic treatment is for thetreatment of estrogen-related gynecomastia. In some embodiments, thetherapeutic treatment is for the treatment of dyspareunia due tomenopause. In some embodiments, the therapeutic treatment is for thetreatment of retroperitoneal fibrosis. In some embodiments, thetherapeutic treatment is for the treatment of idiopathic sclerosingmesenteritis.

In some embodiments, provided herein is a use of a compound of Formula(I), or a tautomer, stereoisomer, pharmaceutically acceptable salt orhydrate thereof, in the preparation of a medicament. In someembodiments, provided herein is a method of inhibiting cell growthcomprising contacting a cell with a compound of Formula (I), or atautomer, stereoisomer, pharmaceutically acceptable salt or hydratethereof. In some embodiments, the cell may express ERα.

In one embodiment, a compound of Formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt or hydrate thereof, isadministered in combination with another therapeutic agent. The othertherapeutic agent can provide additive or synergistic value relative tothe administration of a compound of the present disclosure alone. Thetherapeutic agent can be selected from, for example, hormones andhormonal analogues; signal transduction pathway inhibitors;topoisomerase I inhibitors; topoisomerase II inhibitors; antimetaboliteneoplastic agents; antibiotic neoplastic agents; alkylating agents;anti-microtubule agents; platinum coordination complexes; aromataseinhibitors; and anti-mitotic agents.

In some embodiments, the therapeutic agent may be a hormone or hormonalanalogue. In some embodiments, the therapeutic agent may be a signaltransduction pathway inhibitor. In some embodiments, the therapeuticagent may be a topoisomerase I inhibitor. In some embodiments, thetherapeutic agent may be a topoisomerase II inhibitor. In someembodiments, the therapeutic agent may be an antimetabolite neoplasticagent. In some embodiments, the therapeutic agent may be an antibioticneoplastic agent. In some embodiments, the therapeutic agent may be analkylating agent. In some embodiments, the therapeutic agent may be ananti-microtubule agent. In some embodiments, the therapeutic agent maybe a platinum coordination complex. In some embodiments, the therapeuticagent may be an aromatase inhibitor. In some embodiments, thetherapeutic agent may be an anti-mitotic agent.

In some embodiments, the aromatase inhibitor may be selected fromanastrazole, letrozole, vorozole, fadrozole, exemestane, and formestane.In some embodiments, the aromatase inhibitor is anastrazole. In someembodiments, the aromatase inhibitor may be letrozole. In someembodiments, the aromatase inhibitor may be vorozole. In someembodiments, the aromatase inhibitor may be fadrozole. In someembodiments, the aromatase inhibitor may be exemestane. In someembodiments, the aromatase inhibitor may be formestane.

In some embodiments, the anti-mitotic agent may be selected frompaclitaxel, docetaxel, and Abraxane. In some embodiments, theanti-mitotic agent may be paclitaxel. In some embodiments, theanti-mitotic agent may be docetaxel. In some embodiments, theanti-mitotic agent may be Abraxane.

In some embodiments, a compound of Formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt or hydrate thereof, maybe administered in combination with a hormone or hormonal analog. Insome embodiments, a compound of Formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt or hydrate thereof, maybe administered in combination with a signal transduction pathwayinhibitor. In some embodiments, a compound of Formula (I), or atautomer, stereoisomer, pharmaceutically acceptable salt or hydratethereof, may be administered in combination with an antimetaboliteneoplastic agent. In some embodiments, a compound of Formula (I), or atautomer, stereoisomer, pharmaceutically acceptable salt or hydratethereof, may be administered in combination with a topoisomerase Iinhibitor. In some embodiments, a compound of Formula (I), or atautomer, stereoisomer, pharmaceutically acceptable salt or hydratethereof, may be administered in combination with a topoisomerase IIinhibitor. In some embodiments, a compound of Formula (I), or atautomer, stereoisomer, pharmaceutically acceptable salt or hydratethereof, may be administered in combination with an aromatase inhibitor.In some embodiments, a compound of Formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt or hydrate thereof, maybe administered in combination with one or more anti-cancer agents.

In some embodiments, a compound of Formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt or hydrate thereof, maybe administered in combination with an anti-cancer agent, wherein theanti-cancer agent is tamoxifen. In some embodiments, a compound ofFormula (I), or a tautomer, stereoisomer, pharmaceutically acceptablesalt or hydrate thereof, may be administered in combination with ananti-cancer agent, wherein the anti-cancer agent is fulvestrant.

EXAMPLES

The examples and preparations provided below further illustrate andexemplify the compounds as disclosed herein and methods of preparingsuch compounds. It is to be understood that the scope of the presentdisclosure is not limited in any way by the scope of the followingexamples and preparations.

The chemical entities described herein can be synthesized according toone or more illustrative schemes herein and/or techniques well known inthe art. Unless specified to the contrary, the reactions describedherein take place at atmospheric pressure, generally within atemperature range from about −10° C. to about 200° C. Further, except asotherwise specified, reaction times and conditions are intended to beapproximate, e.g., taking place at about atmospheric pressure within atemperature range of about −10° C. to about 200° C. over a period thatcan be, for example, about 1 to about 24 hours; reactions left to runovernight in some embodiments can average a period of about 16 hours.

Isolation and purification of the chemical entities and intermediatesdescribed herein can be effected, if desired, by any suitable separationor purification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography orthick-layer chromatography, or a combination of these procedures. See,e.g., Carey et al. Advanced Organic Chemistry, 3^(rd) Ed., 1990 NewYork: Plenum Press; Mundy et al., Name Reaction and Reagents in OrganicSynthesis, 2^(nd) Ed., 2005 Hoboken, N.J.: J. Wiley & Sons. Specificillustrations of suitable separation and isolation procedures are givenby reference to the examples hereinbelow. However, other equivalentseparation or isolation procedures can also be used.

In all of the methods, it is well understood that protecting groups forsensitive or reactive groups may be employed where necessary, inaccordance with general principles of chemistry. Protecting groups aremanipulated according to standard methods of organic synthesis (T. W.Greene and P. G. M. Wuts (1999) Protective Groups in Organic Synthesis,3^(rd) Ed., John Wiley & Sons). These groups may be removed at aconvenient stage of the compound synthesis using methods that arereadily apparent to those skilled in the art.

When desired, the (R)- and (S)-isomers of the nonlimiting exemplarycompounds, if present, can be resolved by methods known to those skilledin the art, for example, by formation of diastereoisomeric salts orcomplexes which can be separated, e.g., by crystallization; viaformation of diastereoisomeric derivatives which can be separated, e.g.,by crystallization, gas-liquid or liquid chromatography; selectivereaction of one enantiomer with an enantiomer-specific reagent, e.g.,enzymatic oxidation or reduction, followed by separation of the modifiedand unmodified enantiomers; or gas-liquid or liquid chromatography in achiral environment, e.g., on a chiral support, such as silica with abound chiral ligand or in the presence of a chiral solvent.Alternatively, a specific enantiomer can be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents, or by converting one enantiomer to the other by asymmetrictransformation.

The compounds described herein can be optionally contacted with apharmaceutically acceptable acid to form the corresponding acid additionsalts. Also, the compounds described herein can be optionally contactedwith a pharmaceutically acceptable base to form the corresponding basicaddition salts.

In some embodiments, disclosed compounds can generally be synthesized byan appropriate combination of generally well-known synthetic methods.Techniques useful in synthesizing these chemical entities are bothreadily apparent and accessible to those of skill in the relevant art,based on the instant disclosure. Many of the optionally substitutedstarting compounds and other reactants are commercially available, e.g.,from Millipore Sigma or can be readily prepared by those skilled in theart using commonly employed synthetic methodology.

The discussion below is offered to illustrate certain of the diversemethods available for use in making the disclosed compounds and is notintended to limit the scope of reactions or reaction sequences that canbe used in preparing the compounds provided herein. The skilled artisanwill understand that standard atom valencies apply to all compoundsdisclosed herein in genus or named compound for unless otherwisespecified.

The following abbreviations have the definitions set forth below:

1. BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

2. CbzCl: benzyloxycarbonyl chloride

3. DCE: 1,2-dichloroethane

4. DCM: dichloromethane

5. DIEA or DIPEA: N,N-diisopropylethylamine

6. DMEM: Dulbecco's Modification of Eagle's Medium

7. DMSO: dimethylsulfoxide

8. DMF: N,N-dimethylformamide

9. EDCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

10. ESI-TOF: electrospray ionization time-of-flight mass spectrometry

11. EtOAc: ethyl acetate

12. FBS: fetal bovine serum

13. HOAt: 1-hydroxy-7-azabenzotriazole

14. HPLC: high pressure liquid chromatography

15. HRMS: high resolution mass spectrometry

16. IBX: 2-iodoxybenzoic acid

17. MeOH: methanol

18. MCF-7: Michigan Cancer Foundation-7 breast cancer cell line

19. MTBE: methyl tert-butyl ether

20. NBS: N-bromosuccinimide

21. NMR: nuclear magnetic resonance

22. NCS: N-chlorosuccinimide

23. Pd(dppf)Cl2: bis(diphenylphosphino)ferrocenepalladiumdichloride

24. RPMI: Roswell Park Memorial Institute medium

25. SDS: sodium dodecyl sulfate

26. SFC: Supercritical fluid chromatography

27. TBAB: tetrabutylammonium bromide

28. TBST: tris-buffered saline and Tween 20

29. TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxy

30. p-TSA or TsOH: p-toluenesulfonic acid

31. THF: tetrahydrofuran

Example 1. Synthesis of Compounds of the Present Disclosure

Chemistry General Procedures.

HPLC spectra for all compounds were acquired using an Agilent 1200Series system with DAD detector. Chromatography was performed on a2.1×150 mm Zorbax 300SB-C18 5 μm column with water containing 0.1%formic acid as solvent A and acetonitrile containing 0.1% formic acid assolvent B at a flow rate of 0.4 mL/min. The gradient program was asfollows: 1% B (0-1 min), 1-99% B (1-4 min), and 99% B (4-8 min).High-resolution mass spectra (HRMS) data were acquired in positive ionmode using an Agilent G1969A API-TOF with an electrospray ionization(ESI) source. Nuclear Magnetic Resonance (NMR) spectra were acquired ona Bruker spectrometer with 600 MHz or 400 MHz for proton (¹H NMR) and150 MHz for carbon (¹³C NMR); chemical shifts are reported in (6).Preparative HPLC was performed on Agilent Prep 1200 series with UVdetector set to 254 nm and 220 nm. Samples were injected onto aPhenomenex Luna 75×30 mm, 5 μm, C₁₈ column at room temperature. The flowrate was 40 mL/min. A linear gradient was used with 10% (or 50%) of MeOH(A) in H₂O (with 0.1% TFA) (B) to 100% of MeOH (A). HPLC was used toestablish the purity of target compounds. All final compounds weredetermined to be >95% purity when analyzed according to the HPLC methodsdescribed above.

Compounds with structures of Formula (I) claimed in this application canbe prepared by connecting two ligands through a linker. In general, theclaimed molecules can be approached in a stepwise or modular fashion.The following schemes represent the general methods used in preparingthese compounds. However, the synthesis of Formula (I) is not limited tothese representative methods, as they can also be prepared by thoseskilled in the art of synthetic chemistry.

Synthesis of Compounds 46, 47, 48, 49, 58, 59, 66, 67, 81-83 and 88 canfollow the schemes as described in Scheme 8, 9 and 12.

Example 1: Synthesis ofcis-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione(Compound 36)

Step 1: Preparation of (1-(4-bromophenyl)piperidin-4-yl)methanol

To a mixture of 1-bromo-4-iodobenzene (100 g, 353 mmol, 1.00 eq) andpiperidin-4-ylmethanol (52.8 g, 459 mmol, 1.30 eq) in DMSO (500 mL) wasadded cis-4-hydroxy-L-proline (9.22 g, 70.5 mmol, 0.200 eq), CuI (13.4g, 70.5 mmol, 0.200 eq) and K₃PO₄ (150 g, 0.705 mol, 2.00 eq). Themixture was stirred at 80° C. for 16 hrs. TLC (petroleum ether:ethylacetate=3:1, Rf (starting material)=0.80, Rf (product)=0.30) showed thestarting material was consumed completely. The mixture was poured intoice water (2.50 L), extracted with EtOAc (1.00 L×2). The organic layerwas combined and washed with ammonium hydroxide solution (500 mL×3, 30mL of ammonium hydroxide in 210 mL of H₂O). The organic layer was washedwith brine (500 mL), dried over Na₂SO₄. The mixture was filtered and thefiltrate was concentrated in vacuum to provide(1-(4-bromophenyl)piperidin-4-yl)methanol as an off-white solid.

Step 2: Preparation of 1-(4-bromophenyl)piperidine-4-carbaldehyde

To a solution of (1-(4-bromophenyl)piperidin-4-yl)methanol (80.0 g, 296mmol, 1.00 eq) in DMSO (220 mL) and DIPEA (193 g, 1.49 mol, 261 mL, 5.00eq) was added pyridine-sulfur trioxide (143 g, 901 mmol, 3.00 eq) at0-10° C. The mixture was stirred at 0-10° C. for 2 hrs. TLC (petroleumether:ethyl acetate=1:1, Rf (starting material)=0.30, Rf (product)=0.60)showed the starting material was consumed completely. This mixture waspoured into ice water (2.00 L), extracted with EtOAc (500 mL×3), thecombined organic phase was dried over Na₂SO₄, filtered and concentratedin vacuum. The residue was triturated with petroleum ether:MTBE=10:1(150 mL) and 1-(4-bromophenyl)piperidine-4-carbaldehyde (60.0 g, crude)was obtained as a black brown solid.

Step 3: Preparation of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine

To a solution of 1-(4-bromophenyl)piperidine-4-carbaldehyde (60.0 g, 258mmol, 1.00 eq) and CH(OMe)₃ (82.9 g, 780 mmol, 85.5 mL, 3.00 eq) in MeOH(210 mL) was added TsOH (897 mg, 5.21 mmol, 0.020 eq). Then the mixturewas stirred at 65° C. for 16 hrs. TLC (petroleum ether:ethylacetate=5:1, Rf (starting material)=0.30, Rf (product)=0.50) showed thestarting material was consumed completely. The resulting mixture waspoured into sat. NaHCO₃ (100 mL), extracted with EtOAc (100 mL×3), andthe combined organic phase was dried over Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by flash column silicagel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluentof 0-100 ethyl acetate/petroleum ether gradient, 60 mL/min). The desired1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (70.0 g, crude) wasobtained as a white solid. 1H NMR (400 MHz CDCl₃) δ 7.32 (d, J=8.9 Hz,2H), 6.80 (d, J=8.8 Hz, 2H), 4.08 (d, J=7.2 Hz, 1H), 3.66 (br d, J=12.4Hz, 2H), 3.38 (s, 6H), 2.66 (td, J=12.4, 2.0 Hz, 2H), 1.67-1.91 (m, 3H),1.45 (qd, J=12.4, 4.1 Hz, 2H).

Step 4: Preparation of 3-chloro-1-(2,4-dihydroxyphenyl)propan-1-one

To a solution of resorcinol (230 g, 2.09 mol, 348 mL, 1.00 eq) and3-chloropropanoic acid (249 g, 2.30 mol, 1.10 eq) at 40° C. was addedCF₃SO₃H (1.10 kg, 7.31 mol, 645 mL, 3.50 eq), then the mixture wasstirred at 80° C. for 1 hr. TLC (petroleum ether:ethyl acetate=3:1, Rf(starting material)=0.21, Rf (product)=0.35) showed the startingmaterial was consumed completely. The resulting3-chloro-1-(2,4-dihydroxyphenyl)propan-1-one (419 g, crude) was used tothe next step directly.

Step 5: Preparation of 7-hydroxychroman-4-one

The crude 3-chloro-1-(2,4-dihydroxyphenyl)propan-1-one (419 g, 2.09 mol,1.00 eq) was mixed with NaOH (584 g, 14.6 mol, 7.00 eq) in H₂O (1.59 L),then the mixture was stirred at 0° C. for 30 min. TLC (petroleumether:ethyl acetate=3:1, Rf (starting material)=0.40, Rf (product)=0.60)showed the starting material was consumed completely. The reactionmixture was first adjusted with 6 N HCl to pH about 5, then extractedwith EtOAc (2×1.50 L). The organic layers were combined, dried overNa₂SO₄, filtrated and concentrated under reduced pressure to afforddesired crude product (342 g, crude) as a brown gum.

Step 6: Preparation of 7-(benzyloxy)chroman-4-one

To a solution of 7-hydroxychroman-4-one (342 g, 2.08 mol, 1.00 eq) inDMF (1.50 L), was added K₂CO₃ (575 g, 4.17 mol, 2.00 eq) andbenzylbromide (391 g, 2.29 mol, 272 mL, 1.10 eq), then the mixture wasstirred at 15° C. for 12 hr. TLC (petroleum ether:ethyl acetate=3:1, Rf(starting material)=0.20, Rf (product)=0.50) showed the startingmaterial was consumed completely. The mixture was poured into H₂O (7.50L), extracted with EtOAc (2.00 L×2). The combine organic layer waswashed with brine (2.00 L), dried over Na₂SO₄, filtered and concentratedin vacuum. The residue was purified by column chromatography (SiO₂,petroleum ether:ethyl acetate=15:1 to 8:1) to provide7-(benzyloxy)chroman-4-one (185 g) as a white solid. LCMS m/z 255(M+H)+.

Step 7: Preparation of7-(benzyoxyl)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)chroman-4-ol

To a solution of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (63.0g, 200 mmol, 1 eq) in 2-methyl-tetrahydrofunan (440 mL) was added n-BuLi(2.5 M, 96.2 mL, 1.30 eq), the mixture was stirred at −78° C. for 1 hr,then 7-(benzyloxy)chroman-4-one (50.9 g, 200 mmol, 1.00 eq) was addedand the mixture was stirred at −78° C. for 1 hr. TLC (petroleumether:ethyl acetate=3:1, Rf (starting material)=0.50, Rf (product)=0.15)showed the starting material was consumed completely. The mixture waspoured into H₂O (300 mL), extracted with EtOAc (50.0 mL×2), and thecombined organic layer was washed with brine (50.0 mL), dried overNa₂SO₄, filtered and concentrated in vacuum. The crude product wastriturated with petroleum ether:EtOAc (500 mL) at 15° C. for 30 min toafford7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)chroman-4-ol(72.0 g, crude) a as white solid. 1H NMR (400 MHz, CDCl₃) δ 7.31-7.46(m, 5H), 7.25 (d, 2H), 6.87-6.93 (m, 3H), 6.48-6.53 (m, 2H), 5.04 (s,2H), 4.35-4.42 (m, 1H), 4.20 (dt, J=11.2 Hz, 1H), 4.09 (d, J=7.2 Hz,1H), 3.72 (br d, J=12.0 Hz, 2H), 3.38 (s, 6H), 2.68 (br t, J=11.2 Hz,2H), 2.25 (m, 1H), 2.15 (m, 1H), 2.10 (s, 1H, OH), 1.86 (br d, J=13.2Hz, 2H), 1.75 (ddq, J=11.2 Hz, 1H), 1.46 (br dd, J=12.0 Hz, 2H).

Step 8: Preparation of1-(4-(7-(benzyloxy)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine

To a solution of7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)chroman-4-ol(66.0 g, 134 mmol, 1.00 eq) in MeOH (198 mL), was added TsOH (512 mg,2.70 mmol, 2.07e-2 eq), and the mixture was stirred at 78° C. for 30min. TLC (petroleum ether:ethyl acetate=3:1, Rf (startingmaterial)=0.30, Rf (product)=0.60) showed the starting material wasconsumed completely. The mixture was stirred at 25° C. for 30 min,filtered and the cake was dried in vacuum to afford1-(4-(7-(benzyloxy)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine(60.0 g, crude) as a white solid. 1H NMR (400 MHz, CDCl₃) δ 7.31-7.46(m, 5H), 7.23 (br d, J=8.2 Hz, 2H), 6.92-7.02 (m, 3H), 6.56 (s, 1H),6.50 (dd, J=8.3 Hz, 2.3 Hz, 1H), 5.62 (t, J=4.0 Hz, 1H), 5.05 (s, 2H),4.81 (d, J=3.8 Hz, 2H), 4.11 (d, J=7.1 Hz, 1H), 3.77 (br d, J=12.0 Hz,2H), 3.39 (s, 6H), 2.72 (t, J=12.4 Hz, 2H), 1.88 (br d, J=13.6 Hz, 2H),1.74-1.82 (m, 1H), 1.41-1.53 (m, 2H).

Step 9: Preparation of1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine

To a solution of1-(4-(7-(benzyloxy)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine(60.0 g, 139 mmol, 1.00 eq) and DIEA (36.1 g, 279 mmol, 48.7 mL, 2.00eq) in DMF (300 mL), was added pyridinium tribromide (71.6 g, 223 mmol,1.60 eq) at 0° C., and the mixture was stirred at 15° C. for 1 hr. TLC(petroleum ether:ethyl acetate=3:1, Rf (starting material)=0.50, Rf(product)=0.60) showed the starting material was consumed completely.The mixture was poured into H₂O (700 mL), extracted with EtOAc (300mL×2), and the organic layer was washed with brine (300 mL), dried overNa₂SO₄, filtered and concentrated in vacuum. The residue was purified bycolumn chromatography (SiO₂, petroleum ether:ethyl acetate=30:1 to 0:1)to afford1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine(40.0 g, crude) as a yellow oil. LCMS m/z 550.2 and 552.2 [M+H]+; 1H NMR(400 MHz, CDCl₃) δ 7.30-7.45 (m, 5H), 7.14 (br d, J=8.4 Hz, 2H), 6.98(br d, J=8.4 Hz, 2H), 6.67 (d, J=8.6 Hz, 1H), 6.52 (d, J=1.7 Hz, 1H),6.43 (dd, J=8.7 and 1.7 Hz, 1H), 5.03 (s, 2H), 4.97 (s, 2H), 4.12 (d,J=7.2 Hz, 1H), 3.80 (br d, J=12.4 Hz, 2H), 3.40 (s, 6H), 2.74 (br t,J=11.8 Hz, 2H), 1.89 (br d, J=13.2 Hz, 2H), 1.74-1.84 (m, 1H), 1.43-1.56(m, 2H).

Step 10: Preparation of1-(4-(7-(benzyloxy)-3-phenyl-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine

To a solution of1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine(33.0 g, 59.9 mmol, 1.00 eq) in DMF (140 mL) and H₂O (14 mL), was addedphenylboronic acid (10.9 g, 89.9 mmol, 1.50 eq), K₂CO₃ (16.5 g, 119mmol, 2.00 eq) and Pd(dppf)Cl₂ (855 mg, 1.17 mmol, 0.02 eq), and themixture was stirred at 70° C. for 12 hrs. TLC (petroleum ether:ethylacetate=3:1, Rf (starting material)=0.50, Rf (product)=0.60) showed thestarting material was consumed completely. The mixture was poured intoH₂O (500 mL), extracted with EtOAc (200 mL×2). The combined organiclayer was washed with brine (200 mL), dried over Na₂SO₄, filtered andconcentrated in vacuum. The crude product was triturated with MeOH (100mL) at 25° C. for 30 min to afford1-(4-(7-(benzyoxyl)-3-phenyl-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine(30.0 g, crude) as a gray solid.

Step 11: Preparation ofcis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol

To a solution of1-(4-(7-(benzyloxy)-3-phenyl-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine(30.0 g, 54.7 mmol, 1.00 eq) in THF (30.0 mL) and EtOH (300 mL) wasadded Pd/C (3.00 g, 10.0% purity) and Pd(OH)₂/C (3.00 g, 20.0% purity)under N₂ atmosphere. The suspension was degassed and purged with H₂three times. The mixture was stirred under H₂ (50 psi) at 60° C. for 12hrs. TLC (petroleum ether:ethyl acetate=3:1, Rf (startingmaterial)=0.50, Rf (product)=0.20) showed the starting material wasconsumed completely. The mixture was filtered, and the filtrate wasconcentrated in vacuum. The crude product was triturated with petroleumether:EtOAc=10:1 (50.0 mL) at 25° C. for 30 min to affordcis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-olas an off-white solid. LCMS m/z 460.2 [M+H]+; 1H NMR (400 MHz, CDCl₃) δ7.11-7.20 (m, 3H), 6.82 (d, J=8.3 Hz, 1H), 6.62-6.73 (m, 4H), 6.43-6.51(m, 3H), 6.35 (dd, J=8.2, 2.5 Hz, 1H), 4.77 (br s, 1H, OH), 4.43 (t,J=11.2 Hz, 1H), 4.17-4.27 (m, 2H), 4.08 (d, J=7.4 Hz, 1H), 3.53-3.65 (m,3H), 3.37 (s, 6H), 2.57 (t, J=10.8 Hz, 2H), 1.82 (br d, J=12.8 Hz, 2H),1.66-1.77 (m, 1H), 1.38-1.49 (m, 2H).

Steps 12-15: Preparation of2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dioneHydrochloride

This compound was prepared in four steps as a hydrochloride salt asdescribed in the scheme. LC/MS 343.1 [M+H]+; 1H-NMR (400 MHz, CD₃OD) δppm 7.76 (d, J=8.36 Hz, 1H), 7.47 (s, 1H), 7.35 (dd, J=8.36, 1.54 Hz,1H), 5.09 (br dd, J=12.8, 5.40 Hz, 1H), 3.67-3.74 (m, 4H), 3.37-3.42 (m,4H), 2.63-2.94 (m, 3H), 2.07-2.17 (m, 1H).

Steps 16-17: Preparation ofcis-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione(Compound 36)

To a solution ofcis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol(50 mg, 0.11 mmol) in 2 mL of THF was added 2M aqueous sulfuric acid (2mL, 4 mmol). The mixture was stirred at 70° C. for 30 minutes until allstarting material was consumed. The mixture was adjusted to pH=9 with 1NNaOH solution and then extracted with ethyl acetate (10 mL×3). Thecombined organic layer was washed with brine, dried, filtered andconcentrated under reduced pressure to give a crude product aldehyde (50mg). LC/MS m/z 413.9 [M+H]+. The above crude aldehyde (50 mg, 0.09 mmol)was mixed with2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dionehydrochloride (37.8 mg, 0.1 mmol), TEA (18.2 mg, 0.18 mmol) in DCM (10mL) followed by the addition of MgSO₄ (108 mg, 0.9 mmol). The reactionmixture was stirred at room temperature for 1 hour. Then NaBH(AcO)₃(47.7 mg, 0.225 mmol) was added portion-wise in 3 hours. The reactionmixture was stirred at room temperature overnight. The resulting mixturewas concentrated in vacuum to give a crude product. The crude productwas purified by Prep-TLC with MeOH:DCM=1:10 to give the title compound(19.8 mg, 27.6%). LC/MS m/z 740.3 [M+H]+; 1H NMR (400 MHz, DMSO) δ 11.10(s, 1H, NH), 9.30 (s, 1H, OH), 7.69 (d, J=8.5 Hz, 1H), 7.35 (s, 1H),7.26 (d, J=7.5 Hz, 1H), 7.19-7.14 (m, 3H), 6.78 (d, J=3.2 Hz, 2H),6.69-6.60 (m, 3H), 6.39 (d, J=8.2 Hz, 2H), 6.33-6.27 (m, 2H), 5.08 (dd,1H), 4.33 (t, J=11 Hz, 1H), 4.22-4.17 (m, 2H), 3.60-3.51 (m, 3H), 3.44(br s, 4H), 2.91-2.85 (m, 1H), 2.64-2.48 (m, 8H), 2.20 (br d, J=7.4 Hz,2H), 2.06-1.97 (m, 1H), 1.82-1.75 (m, 2H), 1.74-1.61 (m, 1H), 1.16-1.24(m, 2H); HRMS calculated for C44H45N5O6 exact mass 739.3370, observed[M+1]⁺ 740.3421.

Example 2: Synthesis ofcis-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(2-fluoro-4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione(Compound 87)

Step 1: Preparation of(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methanol

To a solution of compound 1,2-difluoro-4-nitrobenzene (100 g, 628 mmol,69.4 mL, 1.00 eq) and K₂CO₃ (130 g, 942 mmol, 1.50 eq) in DMF (500 mL),was added piperidin-4-ylmethanol (76.0 g, 660 mmol, 1.05 eq) at 0° C.,then the mixture was stirred at 25° C. for 12 hrs. TLC (petroleumether:ethyl acetate=3:1, Rf (starting material)=0.50, Rf (product)=0.30)showed the starting material was consumed completely. The mixture waspoured into H₂O (2.50 L), stirred for 20 min, filtered and the cake wasconcentrated in vacuum to provide(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methanol (158 g, 621 mmol,98.8% yield) as a yellow solid.

Step 2: Preparation of(1-(4-amino-2-fluorophenyl)piperidin-4-yl)methanol

To a solution of (1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methanol (158g, 424 mmol, 1.00 eq) in MeOH (1.00 L) was added Pd/C (1.60 g, 10%purity) under argon. The suspension was degassed under vacuum and purgedwith H₂ several times. The mixture was stirred under H₂ (50 psi) at 50°C. for 12 hr. TLC (petroleum ether:ethyl acetate=3:1, Rf (startingmaterial)=0.30, Rf (product)=0.10) showed the starting material wasconsumed completely. The mixture was filtered and the filtrate wasconcentrated in vacuum to provide(1-(4-amino-2-fluorophenyl)piperidin-4-yl)methanol. as a brown solid.

Step 3: Preparation of (1-(2-fluoro-4-iodophenyl)piperidin-4-yl)methanol

To a solution of (1-(4-amino-2-fluorophenyl)piperidin-4-yl)methanol(90.0 g, 401 mmol, 1.00 eq) in MeCN (360 mL) cooled to 0° C. was addedHCl (12 M, 100 mL, 3.00 eq), then NaNO2 (33.2 g, 481 mmol, 1.20 eq) inH₂O (40.0 mL) was added dropwise at 0° C., the mixture was stirred for0.5 hr followed by the addition of KI (166 g, 1.00 mol, 2.50 eq) in H₂O(100 mL) at 0° C. The mixture was stirred at 15° C. for 11 hrs. TLC(petroleum ether:ethyl acetate=1:1, Rf (starting material)=0.25, Rf(product)=0.10) showed the starting material was consumed completely.The mixture was filtered and the cake was triturated with sat. NaOH (4M,500 mL) at 15° C. for 30 min, filtered, and the cake (brown solid) wasused into the next step. Step 4: Preparation of1-(2-fluoro-4-iodophenyl)piperidine-4-carbaldehyde.

To a solution of NaHCO₃ (46.8 g, 558 mmol, 1.70 eq) and Na₂CO₃ (6.05 g,57.1 mmol, 0.174 eq) in H₂O (750 mL) was added(1-(2-fluoro-4-iodophenyl)piperidin-4-yl)methanol (110 g, 328 mmol, 1eq) in DCM (750 mL), then TBAB (10.6 g, 33.1 mmol, 0.101 eq), TEMPO(1.29, 8.21 mmol, 0.020 eq) and NCS (54.7 g, 410 mmol, 1.00 eq) wereadded at 0° C., the mixture was stirred at 0° C. for 1.5 hrs. TLC(petroleum ether:ethyl acetate=3:1, Rf (starting material)=0.25, Rf(product)=0.50) showed the starting material was consumed completely.The mixture was extracted with DCM (500 mL×2). The combined organiclayer was washed with saturated Na2SO3 solution (200 mL) and brine (200mL), dried over Na2SO4, filtered and concentrated under reduced pressureto give 1-(2-fluoro-4-iodophenyl)piperidine-4-carbaldehyde (90.0 g,crude) as a brown solid.

Step 5: Preparation of4-(dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)piperidine

To a solution of 1-(2-fluoro-4-iodophenyl)piperidine-4-carbaldehyde(90.0 g, 270 mmol, 1.00 eq) in MeOH (600 mL), was added CH(OCH3)3 (43.0g, 405 mmol, 1.50 eq) and TsOH (6.98 g, 40.5 mmol, 0.150 eq), then themixture was stirred at 65° C. for 12 hrs. TLC (petroleum ether:ethylacetate=3:1, Rf (starting material)=0.35, Rf (product)=0.60) showed thestarting material was consumed completely. The pH was adjusted to 9 byprogressively adding sat. NaHCO₃. The mixture was concentrated invacuum, then the mixture was added to H₂O (200 mL), extracted with EtOAc(500 mL×2), the combined organic layer was washed with brine (200 mL),dried over Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by column chromatography (SiO₂, petroleum ether/ethylacetate=30/1 to 10/1) to afford4-(dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)piperidine (90.0 g, 237mmol, 87.7% yield) as a yellow solid.

Step 6: Preparation of7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-4-ol

To a solution of 1-(4-iodo-2-fluorophenyl)-4-(dimethoxymethyl)piperidine(45 g, 118 mmol, 1.00 eq) in 2-methyl-tetrahydrofuran (225 mL), wasadded n-BuLi (2.5 M, 61.5 mL, 1.30 eq) at −65° C., the mixture wasstirred at −65° C. for 0.5 hr, then 7-(benzyoxyl)chroman-4-one (22.5 g,88.9 mmol, 0.750 eq) in 2-methyl-tetrahydrofuran (100 mL) was added at−65° C., and the mixture was stirred at −65° C. for 2.5 hrs. TLC(petroleum ether:ethyl acetate=3:1, Rf (starting material)=0.50, Rf(product)=0.15) showed the starting material was consumed completely.The same reaction was repeated one more time and two reactions werecombined for workup. The mixture was poured into H₂O (300 mL), extractedwith EtOAc (50.0 mL×2), and the combined organic layer was washed withbrine (50.0 ml), dried over Na₂SO₄, filtered and concentrated in vacuumto afford7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-4-ol(85.0 g, crude) as a red solid.

Step 7: Preparation of1-(4-(7-(benzyloxy)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine

To a solution of7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-4-ol(85.0 g, 165 mmol, 1.00 eq) in MeOH (255 mL) was added TsOH (588 mg,3.42 mmol, 0.021 eq) at 15° C. The mixture was stirred at 75° C. for 0.5hr. TLC (petroleum ether:ethyl acetate=3:1, Rf (starting material)=0.30,Rf (product)=0.60) showed the starting material was consumed completely.The mixture was stirred at 25° C. for 30 min, filtered and the cake wasdried in vacuum to provide1-(4-(7-(benzyloxy)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine(75.0 g, 140 mmol, 77.1% yield) as red solid. 1H NMR (400 MHz, CDCl₃) δ7.30-7.46 (m, 5H), 6.88-7.06 (m, 4H), 6.56 (d, J=2.3 Hz, 1H), 6.51 (dd,J=8.6, 2.4 Hz, 1H), 5.64 (t, J=3.9 Hz, 1H), 5.06 (s, 2H), 4.80 (d, J=3.9Hz, 2H), 4.12 (d, J=7.2 Hz, 1H), 3.53 (br d, J=11.6 Hz, 2H), 3.40 (s,6H), 2.68 (br t, J=11.2 Hz, 2H), 1.87 (br d, J=12.8 Hz, 2H), 1.76 (m,1H), 1.45-1.65 (m, 2H).

Step 8: Preparation of1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine

To a solution of1-(4-(7-(benzyloxy)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine(75.0 g, 153 mmol, 1.00 eq) and DIEA (59.0 g, 459 mmol, 80.0 mL, 3.00eq) in DMF (350 mL) was added pyridinium tribromide (73.0 g, 245 mmol,1.60 eq) at ° C. under N₂. The mixture was stirred at 15° C. for 1 hr.TLC (petroleum ether:ethyl acetate=3:1, Rf (starting material)=0.50, Rf(product)=0.60) showed the starting material was consumed completely.The mixture was poured into H₂O (1.00 L), extracted with EtOAc (300 mL)twice, and the organic layer was washed with brine (300 mL), dried overNa₂SO₄, filtered and concentrated in vacuum. The crude product wastriturated with MTBE (250 mL) at room temperature for 30 min to provide1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine(90.0 g, crude) as a red solid. 1H NMR (400 MHz, CDCl₃) δ 7.31-7.49 (m,5H), 6.85-7.06 (m, 3H), 6.63 (m, 1H), 6.53 (d, J=2.20 Hz, 1H), 6.44 (dd,J=8.6, 2.4 Hz, 1H), 5.03 (s, 2H), 4.98 (s, 2H), 4.13 (d, J=7.3 Hz, 1H),3.50-3.62 (m, 2H), 3.40 (s, 6H), 2.71 (br t, J=11.2 Hz, 2H), 1.70-1.93(m, 3H), 1.56 (qd, J=12.0, 3.6 Hz, 2H).

Step 9: Preparation of1-(4-(7-(benzyloxy)-3-phenyl-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine

To a solution of1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine(85.0 g, 148 mmol, 1.00 eq) in DMF (400 mL) and H₂O (40.0 mL), was addedphenylboronic acid (25.4 g, 208 mmol, 1.40 eq), K₂CO₃ (45.7 g, 330 mmol,2.22 eq) and Pd(dppf)Cl2 (2.50 g, 3.429 mmol, 0.023 eq). The mixture wasstirred at 70° C. under N₂ for 12 hrs. TLC (petroleum ether:ethylacetate=3:1, Rf (starting material)=0.50, Rf (product)=0.55) showed thestarting material was consumed completely. The mixture was poured intoH₂O (1.50 L), and stirred at 15° C. for 30 min. The solid was filteredand the cake was dried in vacuum to provide1-(4-(7-(benzyloxy)-3-phenyl-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine(60.0 g, crude) as a red solid. 1H NMR (400 MHz, CDCl₃) δ 7.30-7.49 (m,5H), 7.07-7.22 (m, 3H), 6.98 (d, 2H), 6.72-6.88 (m, 4H), 6.65 (s, 1H),6.50 (d, 1H), 5.06 (br s, 4H), 4.11 (br dd, J=5.6, 1.2 Hz, 1H),3.46-3.53 (m, 2H), 3.39 (s, 6H), 2.63 (t, J=11 Hz, 2H), 1.87 (br d, 2H),1.75 (m, 1H), 1.45-1.63 (m, 2H).

Step 10: Preparation ofcis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol

To a solution of1-(4-(7-(benzyloxy)-3-phenyl-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine(30.0 g, 53.1 mmol, 1.00 eq) in THF (75.0 mL) and EtOH (300.0 mL) wasadded Pd/C (3 g, 10% purity) under N₂ atmosphere. The suspension wasdegassed and purged with H₂ three times. The mixture was stirred underH₂ (50 psi) at 50° C. for 12 hrs. TLC (petroleum ether:ethylacetate=3:1, Rf (starting material)=0.50, Rf (product)=0.20) showed thestarting material was consumed completely. The resulting mixture wasfiltered, and the filtrate was concentrated in vacuum. The same size ofhydrogenation reaction was repeated, and the two reactions were combinedfor purification. The crude product was triturated with petroleumether:EtOAc=10:1 (200 mL) at 25° C. for 30 min to providecis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol(50.0 g, 96.8% purity) as an off-white solid. LCMS m/z 478.2 [M+H]+; 1HNMR (400 MHz, CDC) δ 7.12-7.23 (m, 3H), 6.80 (d, J=8.3 Hz, 1H),6.60-6.73 (m, 3H), 6.46 (d, J=2.4 Hz, 1H), 6.38 (dd, J=8.3, 2.6 Hz, 1H),6.22-6.30 (m, 2H), 4.72 (br s, 1H), 4.41 (t, J=11.2 Hz, 1H), 4.25 (dd,J=10.8, 2.4 Hz, 1H), 4.19 (d, J=5.2 Hz, 1H), 4.09 (d, J=7.4 Hz, 1H),3.54-3.61 (m, 1H), 3.37 (s and m, 8H), 2.54 (br t, J=11.8 Hz, 2H), 1.82(br d, J=12.8 Hz, 2H), 1.65-1.76 (m, 1H), 1.43-1.56 (m, 2H).

Step 11: Preparation ofcis-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(2-fluoro-4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione(Compound 87)

This step of the reaction was carried out using the same method asdescribed in steps 16-17 of Example 1. LC/MS m/z 758.7 [M+H]+; 1H NMR(400 MHz, DMSO) δ 11.10 (s, 1H), 9.36 (s, 1H), 7.69 (d, J=8.2 Hz, 1H),7.35 (s, 1H), 7.26 (d, J=7.7 Hz, 1H), 7.22-7.08 (m, 3H), 6.86-6.64 (m,4H), 6.38-6.26 (m, 3H), 6.15 (d, J=14.0 Hz, 1H), 5.08 (dd, J=13.0, 5.4Hz, 1H), 4.33 (t, J=11 Hz, 1H), 4.26-4.21 (m, 2H), 3.60-3.52 (m, 1H),3.49-3.39 (br s, 4H), 3.27-3.18 (m, 2H), 2.93-2.84 (m, 1H), 2.69-2.48(m, 8H), 2.20 (br d, 2H), 2.07-1.96 (m, 1H), 1.83-1.73 (m, 2H),1.70-1.60 (m, 1H), 1.16-1.24 (m, 2H); HRMS calculated for C44H44FN5O6exact mass 757.3276, observed [M+1]⁺758.3336.

Example 3: Synthesis of(S)-3-(6-fluoro-5-(4-((1-(2-fluoro-4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(Compound 41)

Step 1: Preparation of methyl 2-bromo-4,5-difluorobenzoate

Thionyl chloride (130 g, 1.09 mol) was added slowly to a mixture of2-bromo-4,5-difluorobenzoic acid (200 g, 0.84 mol) in MeOH (600 mL) at10° C., the mixture was stirred at 80° C. for 3 h. TLC showed thereaction was completed. The mixture was cooled to room temperature,concentrated, then partitioned between ethyl acetate and water. Theorganic layer was washed with saturated Na₂CO₃ and brine twice, driedover Na₂SO₄ and concentrated to afford a crude methyl2-bromo-4,5-difluorobenzoate (210 g, yield: 100%) which was used for thenext step without further purification.

Step 2: Preparation of tert-butyl4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

A mixture of methyl 2-bromo-4,5-difluorobenzoate (210 g, 0.84 mol),tert-butyl piperazine-1-carboxylate (234 g, 1.25 mol) and K₂CO₃ (173 g,1.25 mol) in N,N-dimethylacetamide (600 mL) was stirred at 80° C. for 16h. TLC showed the reaction was completed. The mixture was added to water(2 L) and stirred for 10 min followed by the addition of ethyl acetate.The mixture was partitioned between ethyl acetate and water. The organiclayer was washed with water, brine, dried over Na₂SO₄ and concentratedto afford tert-butyl4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate(315.8 g, yield: 90%).

Step 3: Preparation of tert-butyl4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

A mixture of tert-butyl4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate(306 g, 0.73 mol) and CuCN (98 g, 1.09 mol) in DMF (1.2 L) was stirredat 100° C. for 16 h. TLC showed the reaction was completed. The mixturewas cooled to room temperature. Ethyl acetate (2 L) and ammoniumhydroxide (2 L) were added and the mixture was stirred for 30 min. Themixture was filtered. The organic layer was washed with water, driedover Na₂SO₄ and concentrated to afford a crude product (254 g). Thiscrude product was taken into petroleum ether (1 L) at reflux. Themixture was filtered and dried in oven at 50° C. to afford tert-butyl4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate(215 g, yield: 81%).

Step 4: Preparation of tert-butyl4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

To a solution of pyridine (391 g, 4.95 mol), water (200 mL), acetic acid(264 g, 4.4 mol) was added tert-butyl4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate(200 g, 0.55 mol) and Raney-nickel (85% in water, 100 g) at roomtemperature. The resulting mixture was heated to 60° C. Sodiumhypophosphite (292 g in 500 mL water) was added dropwise into themixture. The mixture was stirred for 16 h at 60° C. TLC showed thereaction not completed. The mixture was further stirred for 10 h. Themixture was cooled to room temperature. Ethyl acetate and water wereadded. The mixture was filtered. The organic layer was washed withwater, 1N HCl and brine, dried over Na₂SO₄ and concentrated underreduced pressure to afford a crude product (208 g, crude) which wasfurther purified by silica-gel pad to provide4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate(86.5 g, yield: 43%).

Step 5: Preparation of tert-butyl(S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate(81.5 g, 0.22 mol) in methanol (500 mL) was added tert-butyl(S)-4,5-diamino-5-oxopentanoate (54 g, 0.27 mol) at room temperature.Acetic acid (19.8 g, 0.33 mol) was added at 0° C. followed by theaddition of sodium cyanoborohydride (27.6 g, 0.44 mol) slowly. Themixture was stirred at room temperature for 16 hours. TLC showed thereaction was completed. The mixture was concentrated and partitionedbetween ethyl acetate and water. The organic layer was washed withsaturated citric acid, brine, dried over Na₂SO₄ and concentrated underreduced pressure to afford a crude product which was further purified bysilica-gel pad to give tert-butyl(S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate(80 g, yield: 69%).

Step 6: Preparation of(S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dioneBenzenesulfonic Acid

To a solution of(S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate(67 g, 0.13 mol) in acetonitrile (670 mL) was added benzenesulfonic acid(43 g, 0.26 mol). The mixture was stirred at 80° C. for 16 h. LCMSshowed the reaction was complete. The mixture was cooled to roomtemperature. The mixture was filtered and dried to afford(S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dionebenzenesulfonic acid (56 g, 86%) as off-white solid. ¹H NMR (400 MHz,DMSO-d6) δ 1.94-1.99 (m, 1H), 2.35-2.43 (m, 1H), 2.58-2.62 (m, 1H),2.88-2.91 (m, 1H), 3.30 (br s, 8H), 4.38 (d, J=17.2 Hz, 1H), 4.26 (d,J=17.2 Hz, 1H), 5.08 (dd, J=13.2, 5.2 Hz, 1H), 7.29-7.35 (m, 4H), 7.49(d, J=8.7 Hz, 1H), 7.60 (m, 2H), 8.72 (s, 2H), 10.99 (s, 1H). LCMS m/z347.3 [M+1]⁺.

Step 7: Preparation of(3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol

The racemiccis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-olprepared from step 10 of Compound 87 (50.0 g, 104 mmol) was separated bychiral SFC (column: DAICEL CHIRALCEL OD (250 mm×30 mm, 10 um); mobilephase: [0.1% NH₃H₂O MeOH]; B %: 60%-60%).

The first fraction collected provided(3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol(15.0 g, 99.4% purity) as an off-white solid. [α]_(D) ²⁵=335.8 (1 g/100mL in EtOAc); LCMS m/z 478.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 9.34(s, 1H), 7.12-7.23 (m, 3H), 6.65-6.86 (m, 4H), 6.25-6.35 (m, 3H), 6.13(d, 1H), 4.30 (t, 1H), 4.23 (m, 2H), 4.07 (d, J=6.4 Hz, 1H), 3.53 (m,1H), 3.25 (s, 6H), 3.15-3.24 (m, 2H), 2.42-2.50 (m, 2H), 1.57-1.72 (m,3H), 1.22-1.40 (m, 2H).

The second fraction collected provided(3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol(16.0 g, 98.1% purity) as a brown solid. [α]_(D) ²⁵=−303.9 (0.5 g/100 mLin EtOAc); LCMS m/z 478.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 9.45 (brs, 1H), 7.16 (m, 3H), 6.65-6.80 (m, 4H), 6.25-6.32 (m, 3H), 6.13 (d,J=13.6 Hz, 1H), 4.32 (t, 1H), 4.17-4.27 (m, 2H), 4.07 (d, J=6.4 Hz, 1H),3.55 (m, 1H), 3.25 (s, 6H), 3.16-3.25 (m, 2H), 2.40-2.50 (m, 2H),1.57-1.72 (m, 3H), 1.22-1.37 (m, 2H).

Step 8: Preparation of(S)-3-(6-fluoro-5-(4-((1-(2-fluoro-4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(Compound 41)

The separated (−)-enantiomer from step 7 was first deprotected under theacidic condition and then reacted with the product from step 6 under thesame condition as described in step 11 of Compound 87 preparation. LCMSm/z 762.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.35 (s, 1H),7.43 (d, J=11.6 Hz, 1H), 7.27-7.16 (m, 4H), 6.82-6.72 (m, 3H), 6.68 (d,J=8.2 Hz, 1H), 6.35-6.28 (m, 3H), 6.15 (d, J=14.1 Hz, 1H), 5.08 (dd,1H), 4.43-4.18 (m, 5H), 3.63-3.53 (m, 1H), 3.32-3.30 (m, 2H), 3.26-3.20(m, 2H), 3.12 (br s, 2H), 2.95-2.85 (m, 1H), 2.63-2.48 (m, 7H),2.42-2.32 (m, 1H), 2.22 (br d, 2H), 2.02-1.91 (m, 1H), 1.81-1.73 (m,2H), 1.70-1.61 (m, 1H), 1.27-1.20 (m, 2H); HRMS calculated forC44H45F2N5O5 exact mass 761.3389, observed [M+1]⁺762.3593.

Example 4: Synthesis of(S)-3-(6-fluoro-5-(4-((1-(4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(Compound 42)

Step 1: Preparation of(3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol

The racemiccis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-olprepared in step 11 of Compound 36 (49.2 g, 108 mmol) was separated bychiral SFC (column: DAICEL CHIRALCEL OJ (250 mm×50 mm, 10 um); mobilephase: [0.1% NH₃H₂O MeOH]; B %: 50%-50%, 5.5 min). The first fractioncollected provided(3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-olas an off-white solid (19.0 g, 97.8% purity). [α]_(D) ²=360.4 (1.34g/100 mL in EtOAc); LCMS m/z 460.2 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃) δ7.11-7.20 (m, 3H), 6.82 (d, J=8.3 Hz, 1H), 6.62-6.73 (m, 4H), 6.43-6.51(m, 3H), 6.35 (dd, J=8.2, 2.5 Hz, 1H), 4.84 (br s, 1H, OH), 4.43 (t,J=11.2 Hz, 1H), 4.17-4.27 (m, 2H), 4.08 (d, J=7.4 Hz, 1H), 3.53-3.65 (m,3H), 3.37 (s, 6H), 2.58 (dt, 2H), 1.82 (br d, J=12.8 Hz, 2H), 1.66-1.77(m, 1H), 1.38-1.49 (m, 2H). The second fraction collected provided(3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-olas an off-white solid (19.0 g, 99.8% purity). [α]_(D) ²=−386.8 (0.39g/100 mL in EtOAc); LCMS m/z 460.2 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃) δ7.11-7.20 (m, 3H), 6.82 (d, J=8.3 Hz, 1H), 6.62-6.73 (m, 4H), 6.43-6.51(m, 3H), 6.35 (dd, J=8.2, 2.5 Hz, 1H), 4.79 (br s, 1H, OH), 4.43 (t,J=11.2 Hz, 1H), 4.17-4.27 (m, 2H), 4.07 (d, J=7.4 Hz, 1H), 3.53-3.65 (m,3H), 3.37 (s, 6H), 2.58 (dt, 2H), 1.82 (br d, J=12.8 Hz, 2H), 1.66-1.77(m, 1H), 1.35-1.49 (m, 2H).

Step 2: Preparation of(S)-3-(6-fluoro-5-(4-((1-(4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(Compound 42)

This compound was prepared using the separated (−)-enantiomer from step1 under the same condition as described for the synthesis of compound41. LCMS m/z 744.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.29(s, 1H), 7.43 (d, J=11.3 Hz, 1H), 7.27-7.12 (m, 4H), 6.80-6.74 (m, 2H),6.69-6.59 (m, 3H), 6.38 (d, J=8.1 Hz, 2H), 6.33-6.24 (m, 2H), 5.08 (dd,1H), 4.42-4.15 (m, 5H), 3.67-3.50 (m, 3H), 3.23 (m, 2H), 3.12 (br s,2H), 2.95-2.85 (m, 1H), 2.67-2.50 (m, 7H), 2.41-2.30 (m, 1H), 2.20 (brd, 2H), 2.02-1.90 (m, 1H), 1.82-1.74 (m, 2H), 1.69-1.60 (m, 1H),1.26-1.10 (m, 2H); HRMS calculated for C44H46FN5O5 exact mass 743.3483,observed [M+1]⁺ 744.3681.

Example 5: Synthesis of(S)-3-(5-(4-((1-(2-fluoro-4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(Compound 86)

This compound was prepared using the same method as for the preparationof compound 41. The desired compound was obtained as a neutral form of awhite solid after purification. LCMS m/z 743.7 [M+H]⁺; ¹H NMR (400 MHz,DMSO) δ 10.97 (s, 1H), 9.37 (s, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.17 (m,3H), 7.07 (s, 1H), 7.06 (d, J=8.2 Hz, 1H), 6.84-6.71 (m, 3H), 6.69 (d,J=8.3 Hz, 1H), 6.37-6.27 (m, 3H), 6.16 (br d, J=12 Hz, 1H), 5.06 (dd,J=12.5 Hz, 4.2 Hz, 1H), 4.40-4.18 (m, 5H), 3.57 (m, 1H), 3.32-3.17 (m,6H), 2.96-2.87 (m, 1H), 2.60-2.48 (m, 7H), 2.40-2.33 (m, 1H), 2.22 (brd, 2H), 2.00-1.90 (br d, 1H), 1.80-1.75 (m, 2H), 1.70-1.60 (m, 1H),1.28-1.20 (m, 2H); HRMS calculated for C₄₄H₄₆FN5O5 exact mass 743.3483,observed [M+1]⁺ 744.3567.

Example 6: Synthesis of(S)-3-(5-(4-((1-(2-fluoro-4-((3R,4S)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(Compound 45)

This compound was prepared using the same method as for the preparationof compound 41. LCMS m/z 743.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 10.97(s, 1H), 9.37 (s, 1H), 7.53 (d, J=7.4 Hz, 1H), 7.20-7.06 (m, 5H),6.82-6.78 (m, 2H), 6.78-6.72 (m, 1H), 6.69 (d, J=8.3 Hz, 1H), 6.34-6.29(m, 3H), 6.16 (d, J=14.3 Hz, 1H), 5.06 (dd, J=13.2, 4.8 Hz, 1H),4.43-4.09 (m, 5H), 3.59-3.54 (m, 1H), 3.34-3.19 (m, 6H), 2.94-2.86 (m,1H), 2.69-2.48 (m, 7H), 2.46-2.31 (m, 1H), 2.20 (br, 2H), 1.98-1.92 (m,1H), 1.85-1.60 (m, 3H), 1.29-1.20 (m, 2H); HRMS calculated forC44H46FN5O5 exact mass 743.3483, observed [M+1]+744.3567.

Example 7: Synthesis of(S)-3-(5-(4-((1-(4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(Compound 33)

This compound was prepared using the same method as for the preparationof compound 41. LCMS m/z 725.7 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 10.98(s, 1H), 9.31 (s, 1H), 7.53-7.51 (m, 1H), 7.25-7.02 (m, 5H), 6.77 (m,2H), 6.73-6.60 (m, 3H), 6.40 (d, J=8.3 Hz, 2H), 6.33-6.25 (m, 2H), 5.06(dd, 1H), 4.39-4.31 (m, 2H), 4.26-4.17 (m, 3H), 3.64-3.50 (m, 3H),3.28-3.25 (br s, 4H), 2.94-2.89 (m, 1H), 2.64-2.48 (m, 7H), 2.41-2.33(m, 1H), 2.19 (br, 2H), 2.00-1.93 (m, 1H), 1.86-1.60 (m, 3H), 1.29-1.12(m, 2H); HRMS calculated for C44H47N5O5 exact mass 725.3577, observed[M+1]⁺ 726.3675.

Example 8: Synthesis of(S)-3-(5-(4-((1-(4-((3R,4S)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(Compound 34)

This compound was prepared using the same method as for the preparationof compound 41. LCMS m/z 725.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 10.97(s, 1H), 9.32 (s, 1H), 7.62-7.58 (m, 1H), 7.34-7.30 (m, 1H), 7.19-7.06(m, 4H), 6.83-6.74 (m, 2H), 6.72-6.54 (m, 3H), 6.40 (d, J=7.5 Hz, 2H),6.35-6.20 (m, 2H), 5.07 (br d, J=8.8 Hz, 1H), 4.39-4.30 (m, 2H),4.27-4.14 (m, 3H), 3.64-3.51 (m, 3H), 3.31-3.27 (m, 4H), 2.94-2.87 (m,1H), 2.70-2.54 (m, 7H), 2.40-2.31 (m, 1H), 2.24-2.15 (m, 2H), 2.03-1.65(m, 4H), 1.30-1.20 (m, 2H); HRMS calculated for C44H47N5O5 exact mass725.3577, observed [M+1]⁺ 726.3702.

Example 9: Synthesis ofcis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3-phenylchroman-4yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(Compound 32)

This compound was prepared using the same method as for the preparationof compound 41. LCMS m/z 725.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 10.97(s, 1H), 9.31 (s, 1H), 7.62-7.51 (m, 1H), 7.23-7.04 (m, 5H), 6.81-6.74(m, 2H), 6.71-6.58 (m, 3H), 6.39 (d, J=8.1 Hz, 2H), 6.32 (d, J=2.2 Hz,1H), 6.31-6.26 (m, 1H), 5.06 (dd, J=13.1, 4.4 Hz, 1H), 4.34 (t, J=11.1Hz, 2H), 4.28-4.15 (m, 3H), 3.66-3.47 (m, 3H), 3.33-3.26 (m, 4H),2.96-2.86 (m, 1H), 2.70-2.48 (m, 7H), 2.46-2.31 (m, 1H), 2.20 (br s,2H), 2.02-1.60 (m, 4H), 1.30-1.15 (m, 2H); HRMS calculated forC44H47N5O5 exact mass 725.3577, observed [M+1]⁺ 726.3641.

Example 10:cis-(S)-3-(5-(4-((1-(2-fluoro-4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(Compound 85)

This compound was prepared using the same method as for the preparationof compound 41. LCMS m/z 744.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 10.96(s, 1H), 9.37 (s, 1H), 7.57-7.49 (m, 1H), 7.21-7.04 (m, 5H), 6.83-6.67(m, 4H), 6.37-6.27 (m, 3H), 6.16 (d, J=14.6 Hz, 1H), 5.06 (dd, J=13.3,5.0 Hz, 1H), 4.41-4.16 (m, 5H), 3.59-3.54 (m, 1H), 3.34-3.16 (m, 6H),2.95-2.86 (m, 1H), 2.69-2.48 (m, 7H), 2.44-2.33 (m, 1H), 2.20 (br s,2H), 1.99-1.90 (m, 1H), 1.82-1.74 (m, 2H), 1.72-1.60 (m, 1H), 1.25-1.15(m, 2H); HRMS calculated for C44H46FN5O5 exact mass 743.3483, observed[M+H]⁺ 744.3530.

Example 11: Synthesis ofcis-(S)-3-(5-(4-((1-(2-fluoro-4-(3-(4-fluoro-3-methylphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-done(Compound 60)

Step 1: Preparation of1-(4-(7-(benzyloxy)-3-(4-fluoro-3-methylphenyl)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine

To a solution of1-{4-[7-(benzyloxy)-3-bromo-2H-chromen-4-yl]-2-fluorophenyl}-4-(dimethoxymethyl)piperidine(200 mg, 0.35 mmol), (4-fluoro-3-methylphenyl)boranediol (80.82 mg, 0.52mmol) and potassium carbonate (145.12 mg, 1.05 mmol) in DMF and H₂O (10mL/10 mL) stirred under nitrogen atmosphere at room temperature wasadded 1,1′-Bis(diphenylphosphino)ferrocenepalladiumdichloride (25.60 mg,0.034 mmol). The reaction mixture was stirred at 90° C. under nitrogenatmosphere for 12 hours. The resulting mixture was evaporated in vacuoto give the crude product which was dissolved in DCM (200 mL), washedwith water (20 mL), and evaporated in vacuo. The resulting residue waspurified by preparative TLC (petroleum ether/ethyl acetate=2:1) toobtain desired product as a brown solid (150 mg, 0.29 mmol, 71.3%yield).

Step 2: Preparation ofcis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-(4-fluoro-3-methylphenyl)chroman-7-ol

To a solution of1-(4-(7-(benzyloxy)-3-(4-fluoro-3-methylphenyl)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine(130 mg, 0.26 mmol) in THF (20 mL) stirred at room temperature was addedpalladium/carbon (553.38 mg, 5.2 mmol). The reaction mixture was stirredunder hydrogen atmosphere at room temperature for 1 hour. The reactionmixture was filtered, and the filtrate was concentrated to give thedesired product as a yellow solid (130 mg, 0.25 mmol, 85.3% yield). LCMSm/z 509.7 [M+1]⁺.

Step 3: Preparation ofcis-(S)-3-(5-(4-((1-(2-fluoro-4-(3-(4-fluoro-3-methylphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(Compound 60)

A solution of4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-(4-fluoro-3-methylphenyl)chroman-7-ol(100 mg, 0.2 mmol)) in THF (5 mL) and water (5 ml, with 10% H₂SO₄) wasstirred at 70° C. for 1 h. The reaction mixture was dissolved in DCM(200 mL), adjusted pH to 10 with aqueous sodium hydroxide solution (2M), and the organic layer was evaporated in vacuo to give desiredproduct as a yellow solid (80 mg, 0.17 mmol, 86.3% yield). LCMS m/z463.7 [M+1]⁺. To this solid (30 mg, 0.06 mmol) was added(S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dionebenzenesulfonate (29.19 mg, 0.06 mmol) and triethylamine (30.35 mg, 0.3mmol) in DCM (5 mL). The mixture was stirred at room temperaturefollowing the addition of MgSO₄ (72.00 mg, 0.60 mmol). The reactionmixture was further stirred at room temperature for 2 h followed by theaddition of sodium triacetoxyborohydride portion-wise (38.15 mg, 0.18mmol) at 0° C. The resulting mixture was stirred at room temperature for2 h and then filtered. The filtrate was evaporated in vacuo to give thecrude product which was purified by preparative TLC (DCM:MeOH=10:1) toobtain the desired product as white solid (20 mg, 0.03 mmol, 50.0%yield). LCMS m/z 775.5 [M+1]⁺; ¹H NMR (400 MHz, DMSO) δ=10.95 (s, 1H),9.36 (s, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.10-7.01 (m, 2H), 6.93 (t, J=9.0Hz, 1H), 6.77 (t, J=8.8 Hz, 1H), 6.68 (d, J=8.2 Hz, 1H), 6.64-6.59 (m,2H), 6.36-6.25 (m, 3H), 6.20 (d, J=14.1 Hz, 1H), 5.06 (dd, 1H),4.36-4.12 (m, 5H), 3.59-3.47 (m, 1H), 3.30-3.19 (m, 6H), 2.90-2.86 (m,1H), 2.68-2.48 (m, 7H), 2.38-2.29 (m, 1H), 2.23-2.20 (br d, 2H), 2.08(s, 3H), 2.01-1.92 (m, 1H), 1.79-1.76 (m, 2H), 1.70-1.62 (m, 1H),1.26-1.15 (m, 2H); HRMS calculated for C45H47F2N5O5 exact mass 775.3545,observed [M+1]⁺ 776.3584

Example 12: Synthesis ofcis-(S)-3-(5-(4-((1-(2-fluoro-4-(7-hydroxy-3-(m-tolyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(Compound 52)

This compound was synthesized according to the same procedure asdescribed in Example 11. LC/MS: 757.5 [M+1]⁺; ¹H NMR (400 MHz, DMSO)δ=10.95 (s, 1H), 9.35 (s, 1H), 7.52 (d, J=8.1 Hz, 1H), 7.16-7.02 (m,3H), 6.98 (d, J=7.8 Hz, 1H), 6.75 (t, J=8.9 Hz, 1H), 6.68 (d, J=8.2 Hz,1H), 6.58 (d, J=7.4 Hz, 1H), 6.51 (s, 1H), 6.30-6.24 (m, 3H), 6.16 (d,J=13.9 Hz, 1H), 5.06 (dd, 1H), 4.38-4.10 (m, 5H), 3.52-3.47 (m, 1H),3.30-3.20 (m, 6H), 2.95-2.87 (m, 1H), 2.72-2.48 (m, 7H), 2.42-2.30 (m,1H), 2.22-2.19 (br, 2H), 2.15 (s, 3H), 1.99-1.90 (m, 1H), 1.78 (m, 2H),1.70-1.63 (m, 1H), 1.25-1.10 (m, 2H); HRMS calculated for C45H48FN5O5exact mass 757.3639, observed [M+1]⁺ 758.3681.

Example 13: Synthesis ofcis-(S)-3-(5-(4-((1-(4-(3-(3,4-difluorophenyl)-7-hydroxychroman-4-yl)-2-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(Compound 84)

This compound was synthesized according to the same procedure asdescribed in Example 11. LC/MS: m/z 779.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO)δ=10.95 (s, 1H), 9.38 (s, 1H), 7.53-7.51 (m, 1H), 7.28-7.21 (m, 1H),7.08-7.04 (m, 2H), 6.88-6.74 (m, 2H), 6.69-6.66 (m, 2H), 6.34-6.23 (m,4H), 5.06 (dd, 1H), 4.35-4.15 (m, 5H), 3.65-3.54 (m, 1H), 3.33-3.23 (m,6H), 2.98-2.84 (m, 1H), 2.62-2.41 (m, 7H), 2.38-2.34 (m, 1H), 2.20 (brd, 2H), 2.03-1.93 (m, 1H), 1.80-1.69 (m, 2H), 1.68-1.60 (m, 1H),1.26-1.16 (m, 2H); HRMS calculated for C44H44F3N5O5 exact mass 779.3295,observed [M+1]⁺ 780.3345.

Example 14: Synthesis ofcis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(Compound 56)

Step 1: Preparation of1-(4-(7-(benzyloxy)-3-(3-methoxyphenyl)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine

To a solution of1-{4-[7-(benzyloxy)-3-bromo-2H-chromen-4-yl]phenyl}-4-(dimethoxymethyl)piperidine(100 mg, 0.18 mmol), 3-methoxyphenylboronic acid (41.02 mg, 0.27 mmol)and potassium carbonate (74.63 mg, 0.54 mmol) in DMF/H₂O (20 mL,DMF/H₂O=5:1) stirred under nitrogen at room temperature was added1,1′-Bis(diphenylphosphino)ferrocenepalladiumdichloride (26.34 mg, 0.036mmol). The reaction mixture was stirred under nitrogen at 60° C. for 5hours. The reaction mixture was filtered and evaporated in vacuo to givea crude product. The crude product was dissolved in DCM (200 mL), washedwith water (20 mL), and the organic layer was dried over sodium sulfate,filtered and evaporated in vacuo. The resulting residue was purified bypreparative TLC (PE:EA-5:1) to give the desired product (80 mg, 0.14mmol, 76.1% yield) as yellow solid. LC/MS: 578.1 [M+1]⁺.

Step 2: Preparation ofcis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(3-methoxyphenyl)chroman-7-ol

To a solution of1-{4-[7-(benzyloxy)-3-(3-methoxyphenyl)-2H-chromen-4-yl]phenyl}-4-(dimethoxymethyl)piperidine(100 mg, 0.17 mmol) in THF (15 mL) stirred under hydrogen at roomtemperature was added palladium/carbon (180 mg). The reaction mixturewas stirred at room temperature for 24 hours. The reaction mixture wasfiltered and evaporated in vacuo to give the desired product (80 mg,0.16 mmol, 96.1%) as yellow solid. LC/MS: 489.9 [M+1]⁺.

Step 3: Preparation ofcis-1-(4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidine-4-carbaldehyde

A solution ofcis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(3-methoxyphenyl)chroman-7-ol(100 mg, 0.2 mmol) in THF/H₂SO₄ (10% aq) (20 mL, THF/H₂SO₄=1/1) wasstirred at 70° C. for 2 hours. The reaction mixture was adjusted to pHabout 12 with sodium hydroxide solution (2 mol/L), extracted with DCM(200 mL), dried over sodium sulphate, and evaporated in vacuo to givethe desired product (80 mg, 0.18 mmol, 88% yield) as yellow solid.LC/MS: 443.3[M+1]⁺.

Step 4: Preparation ofcis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(Compound 56)

A solution ofcis-1-(4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidine-4-carbaldehyde(50 mg, 0.11 mmol),(S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dionebenzenesulphonic acid (24.32 mg, 0.05 mmol), TEA (0.25 mmol) and MgSO₄(60 mg, 0.5 mmol) in DCM (5 mL) was stirred under nitrogen at roomtemperature for 30 minutes. Then sodium triacetoxyborohydride (31.79 mg,0.15 mmol) was added at 0° C. portion-wise. The reaction mixture wasstirred at room temperature for 2 hours. The reaction mixture wasfiltered, the organic layer was washed with water, extracted with DCM(50 mL) to give the crude product. The residue was purified bypreparative TLC (DCM:MeOH-10:1) to give the desired product (45 mg, 0.06mmol, 53%) as a white solid. LC/MS: 756.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO)δ 10.95 (s, 1H), 9.27 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.15-6.99 (m,3H), 6.74-6.59 (m, 4H), 6.42 (d, J=8.6 Hz, 2H), 6.37 (d, J=7.6 Hz, 1H),6.34-6.16 (m, 3H), 5.06 (dd, 1H), 4.41-4.15 (m, 5H), 3.61-3.52 (m, 5H),3.50-3.44 (m, 1H), 3.28 (br s, 4H), 2.98-2.84 (m, 1H), 2.66-2.51 (m,7H), 2.37-2.31 (m, 1H), 2.19 (br d, 2H), 2.02-1.90 (m, 1H), 1.80-1.73(m, 2H), 1.69-1.60 (m, 1H), 1.25-1.16 m, 2H); HRMS calculated forC45H49N5O6 exact mass 755.3683, observed [M+H]⁺ 756.3753.

Example 15: Synthesis ofcis-(S)-3-(5-(4-((1-(4-(3-(4-fluoro-3-methoxyphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-done(Compound 63)

This compound was prepared using the same method as described in Example14 except 4-fluoro-3-methylphenylboronic acid was used. The crudeproduct from the final reductive amination step was purified bypreparative TLC to give the desired compound (65 mg, 0.084 mmol, 38.9%yield) as a white solid. LC/MS: 773.6 [M+1]⁺; ¹H NMR (400 MHz, DMSO) δ10.95 (s, 1H), 9.29 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.12-7.03 (m, 2H),6.98 (dd, J=11.5, 8.3 Hz, 1H), 6.68 (dd, J=8.5, 2.5 Hz, 3H), 6.44 (d,J=8.5 Hz, 2H), 6.41-6.33 (m, 2H), 6.33-6.25 (m, 2H), 5.05 (dd, J=13.2,5.0 Hz, 1H), 4.37-4.25 (m, 2H), 4.24-4.18 (m, 1H), 4.18-4.10 (m, 2H),3.61-3.48 (m, 6H), 3.28 (br s, 4H), 2.96-2.83 (m, 1H), 2.64-2.51 (m,7H), 2.46-2.29 (m, 1H), 2.20 (br s, 2H), 2.01-1.93 (m, 1H), 1.83-1.74(m, 2H), 1.73-1.63 (br, 1H), 1.27-1.12 (m, 2H); HRMS calculated forC45H48FN5O6 exact mass 773.3589, observed [M+1]⁺ 774.3818.

Example 16: Synthesis ofcis-(S)-3-(6-fluoro-5-(4-((1-(4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(Compound 74)

This compound was prepared using the same method as described in Example14 except(S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dionebenzenesulfonate was used in the final step of reductive amination. Thecrude product was purified by preparative TLC (DCM:MeOH-10:1) to givethe desired product (25 mg, 48% yield) as white solid. LC/MS: 774.1[M+1]⁺; ¹H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.28 (s, 1H), 7.42 (d,J=11.6 Hz, 1H), 7.22 (d, J=7.3 Hz, 1H), 7.05 (t, J=7.9 Hz, 1H),6.75-6.58 (m, 4H), 6.45-6.33 (m, 3H), 6.30-6.15 (m, 3H), 5.08 (dd, 1H),4.38-4.09 (m, 5H), 3.58 (s, 3H), 3.57-3.52 (m, 2H), 3.52-3.43 (m, 1H),3.21-3.04 (m, 4H), 2.99-2.85 (m, 1H), 2.69-2.53 (m, 7H), 2.49-2.28 (m,1H), 2.20 (br d, 2H), 2.02-1.94 (m, 1H), 1.80-1.60 (m, 3H), 1.30-1.10(m, 2H); HRMS calculated for C45H48FN5O6 exact mass 773.3589, observed[M+1]⁺ 774.3688.

Example 17: Synthesis ofcis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3-(4-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(Compound 89)

This compound was prepared using the same method as described in Example14 except 4-methoxyphenylboronic acid was used. The crude product fromthe final step of reductive amination was purified by preparative TLC(DCM:MeOH-5:1) to give the desired compound as a white solid. LC/MS:756.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO) 6-10.94 (s, 1H), 9.26 (s, 1H), 7.52(d, J=8.5, 1H), 7.05 (m, 2H), 6.79-6.56 (m, 7H), 6.40 (d, J=8.6, 2H),6.33-6.23 (m, 2H), 5.08-5.01 (m, 1H), 4.36-4.11 (m, 5H), 3.68 (s, 3H),3.60-3.52 (m, 2H), 3.48-3.42 (m, 1H), 3.31-3.25 (m, 4H), 2.95-2.84 (m,1H), 2.67-2.42 (m, 7H), 2.46-2.28 (m, 1H), 2.19 (br d, 2H), 2.00-1.92(m, 1H), 1.77 (m, 2H), 1.69-1.63 (m, 1H), 1.27-1.10 (m, 2H); HRMScalculated for C45H49N5O6 exact mass 755.3683, observed [M+1]⁺ 756.3763.

Example 18: Synthesis ofcis-(S)-3-(6-fluoro-5-(4-((1-(4-(7-hydroxy-3-(4-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(Compound 90)

This compound was prepared using the same method as described in Example17 except(S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dionebenzenesulfonate was used in the final step of reductive amination. Thecrude product was purified by preparative TLC (DCM:MeOH-10:1) to givedesired compound as a white solid. LC/MS: 774.2 [M+1]⁺; ¹H NMR (400 MHz,DMSO) δ 10.98 (s, 1H), 9.30 (s, 1H), 7.43 (d, J=11.5 Hz, 1H), 7.24 (d,J=7.3 Hz, 1H), 6.77-6.57 (m, 7H), 6.40 (d, J=8.5 Hz, 2H), 6.34-6.20 (m,2H), 5.05 (dd, 1H), 4.45-4.12 (m, 5H), 3.68 (s, 3H), 3.58-3.48 (m, 3H),3.26-3.05 (m, 4H), 2.95-2.87 (m, 1H), 2.69-2.46 (m, 7H), 2.45-2.28 (m,1H), 2.22 (br, 2H), 2.03-1.95 (m, 1H), 1.79-1.65 (m, 3H), 1.30-1.16 (m,2H); HRMS calculated for C45H48FN5O6 exact mass 773.3589, observed[M+1]⁺ 774.3648.

Example 19: ERα Degradative Activity of Compounds of the PresentDisclosure in T47D, MQF7 and CAMA1 Cells

T47D cells were plated in 24-well plates at 1.5×10⁵ cells/well in theRPMI growth medium containing 10% FBS and 1× Penicillin Streptomycin.MCF7 cells were plated in 24-well plates at 1.5×10⁵ cells/well in theDMEM growth medium containing 10% FBS and 1× Penicillin Streptomycin.CAMA1 cells were plated in 24-well plates at 2×10⁵ cells/well in theRPMI growth medium containing 20% FBS and 1× Penicillin Streptomycin.They were then incubated at 37° C. overnight. The following day, thetest compound was administered to the cells by using 1000× compoundstock solution prepared in DMSO at various concentrations. Afteradministration of the compound, the cells were then incubated at 37° C.for 6 hours.

Upon completion, the cells were washed with PBS and protein wascollected in Laemmli sample buffer (1×; VWR International). Proteins incell lysate were separated by SDS-PAGE and transferred to Odysseynitrocellulose membranes (Licor) with Iblot® dry blotting transfersystem (ThermoFisher). Nonspecific binding was blocked by incubatingmembranes with Intercept Blocking Buffer (Licor) for 1 hour at roomtemperature with gentle shaking. The membranes were then incubatedovernight at 4° C. with Primary antibodies rabbit anti-ER (CellSignaling, 8644) and mouse anti-GAPDH (1:5,000, Santa CruzBiotechnology, sc-47724) diluted in Intercept Blocking Buffer containing0.1% Tween 20. After washing 3 times with TBS-T, the membranes wereincubated with IRDye® 800CW goat anti-mouse IgG (1:20,000, Licor) orIRDye® 800CW goat anti-rabbit IgG (1:20,000, Licor) for 1 hour. AfterTBS-T washes, membranes were rinsed in TBS and scanned on Odyssey® CLxImaging System (Licor). The bands were quantified using Image Studio™Software (Licor).

FIGS. 1A to 1D illustrate the ERα degradative activity of exemplaryCompounds 85, 60, 32 and 52 of the present disclosure in a T47D cellline 6 hours after administration. FIGS. 2A and 2B illustrate the ERαdegradative activity of exemplary Compounds 87 and 84 of the presentdisclosure in a T47D cell line 6 hours after administration. FIGS. 4Aand 4B illustrate the ERα degradative activity of exemplary Compounds 86and 33 of the present disclosure in a T47D cell line 6 hours afteradministration. FIG. 6A to 6C illustrate the ERα degradative activity ofexemplary Compounds 41, 42 and 63 of the present disclosure in a T47Dcell line 6 hours after administration. FIG. 7A to 7D illustrate the ERαdegradative activity of exemplary Compounds 89, 56, 90 and 74 of thepresent disclosure in a T47D cell line 6 hours after administration.

Table 3 illustrates the ERα degradative activity of exemplary compoundsof the present disclosure in T47D cell line 6 hours afteradministration.

TABLE 3 ERα degradative activity of exemplary compounds in T47D cellline Compound # DC50 (nM) in T47D 32 2.4 33 0.3 34 >100 36 >10 41 4 421.1 45 >100 52 5.6 56 1.7 60 6.5 63 2.1 74 7.3 84 9.3 85 3 86 0.5 8712.6 89 0.7 90 9.6

FIGS. 3A and 3B illustrate the ERα degradative activity of exemplaryCompounds 86 and 33 of the present disclosure in a MCF7 cell line 6hours after administration.

FIGS. 5A and 5B illustrate the ERα degradative activity of exemplaryCompounds 86 and 33 of the present disclosure in a CAMA1 cell line 6hours after administration.

The many features and advantages of the present disclosure are apparentfrom the detailed specification, and thus itis intended by the appendedclaims to cover all such features and advantages of the presentdisclosure that fall within the true spirit and scope of the presentdisclosure. Further, since numerous modifications and variations willreadily occur to those skilled in the art, itis not desired to limit thepresent disclosure to the exact construction and operation illustratedand described and accordingly, all suitable modifications andequivalents may be resorted to, falling within the scope of the presentdisclosure.

Moreover, those skilled in the art will appreciate that the conceptionupon which this disclosure is based may readily be used as a basis fordesigning other structures, methods, and systems for carrying out theseveral purposes of the present disclosure. Accordingly, the claims arenot to be considered as limited by the foregoing description orexamples.

What is claimed is:
 1. A process for the preparation of a compoundchosen from the following chemical structures:

and stereoisomers, and pharmaceutically acceptable salts thereof,wherein: X is chosen from H and F, X₁ and X₂ are independently chosenfrom H, F, OCH₃, CH₃, and CF₃, R is chosen from H and F, comprising thesteps of: a) reacting

with Tf₂O and an organic base in an organic solvent to obtainintermediate

b) mixing the intermediate

from step a) with

in the presence of a palladium catalyst,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) and a base in anorganic solvent to obtain intermediate

c) deprotecting the intermediate

from step b) with an acid to obtain an aldehyde product; and d)reductive amination of the aldehyde product with an intermediate chosenfrom,

in the presence of a reducing agent.
 2. The process according to claim1, wherein the organic base used in step a) is N,N-diisopropylethylamine(DIEA).
 3. The process according to claim 1, wherein the palladiumcatalyst used in step b) is Pd(OAc)₂.
 4. The process according to claim1, wherein the acid used in step c) is a sulfuric acid.
 5. The processaccording to claim 1, wherein the reducing agent used in step d) isNaBH(AcO)₃.
 6. The process according to claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 7. The process accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 8. The process accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 9. The process accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.